How surgical innovation will enhance patient outcomes · John Heon, PhD: Professor of English and...

SPRING 2011 | SYNAPSE | 1

PENN’S UNDERGRADUATE MEDICAL CONNECTION

ON THE CUTTING EDGEHow surgical innovation will enhance patient outcomes

Compassionate Care in Pediatric Oncology

Prenatal prevention: Genetic Diagnostics

Skunkworks: Driving Pharma R&D

2 | SYNAPSE | SPRING 2011

I am proud to present the Spring 2011 issue of SYNAPSE: Penn’s Undergraduate Medical Connection. The theme of our third issue is “Surgical Innovation: On the Cutting Edge.” Recent advances in medical robotics have helped to improve surgical performance. As explored in this issue, the da Vinci became the first FDA-approved robotic surgical system at the turn of the millennium, representing a breakthrough in surgical performance and offering unprecedented precision and minimal invasiveness. Today however, the clinical use of robots still remains limited, due primarily to cost limitations and the steep learning curve associated with the new technology. The integration of sensor and visual imaging technology with robotic surgical systems promises to improve the haptic and visual responses of the surgeon, allowing for the performance of more delicate procedures. Penn remains at the forefront of research into medical robotics and boasts one of the best robot-assisted surgical programs in the world. Beyond robotic surgery, the engineering of individualized grafts and partial bone marrow irradiation for transplant patients are explored in this issue as alternatives to traditional immunosuppressive therapy. Finally, novel techniques in neurosurgery and laryngeal transplantation are also investigated. The past semester has been particularly eventful for us, and there has never been a more exciting time to be involved in SYNAPSE. As the recipient of four student publication awards administered by Pubco and sponsored by the New York Times, we feel fortunate to be recognized as the “Best Academic Interest Magazine” at Penn, based upon the quality of our inaugural issue in Spring 2010. Furthermore, our recent corporate sponsorship agreement with Kaplan will help provide financial sustainability for the publication, and we look forward to a successful partnership in the future. These developments are a testament to the dedication to our student leaders and writers, particularly the Executive board. Finally, two of our graduating student leaders deserve special mention. As founding members of SYNAPSE, Meera Ragavan and Elise Dihlmann Malzer have helped shape the vision of the publication since its inception two years ago, serving as Executive Vice President and Executive Editor, respectively. We are deeply grateful for their unfaltering commitment to SYNAPSE, and we wish them all the best after graduation.

Nicholas WilcoxEditor-in-Chief and Founder

Surgical Innovation: On the Cutting EdgeEXECUTIVE BOARD

Editor-in-Chief: Nicholas Wilcox Executive Vice President: Cary KraftExecutive Editor: Elizabeth SaionzExecutive Editor: Amit SahaVP of Design: Jaclyn ChenVP of Design: Diana LuVP of Finance: Anand GopalVP of Technology: Joshua Sherman

GENERAL BOARDS

Associate EditorsGabby Abrishamian-GarciaNuvid BhuiyanAlexandra Cooper-PonteMichael LaiRegina LamJenny MaLauren MathiasReshmi OberoiAvanthi RaghavanAlyssa TrochtenbergLinda Yin

Photo EditorFrances Hu

ADVISORY BOARDKent Bream, MD: Assistant Professor of Clinical Family Medicine and Community Health, Hospital of the University of PennsylvaniaPhyllis Dennery, MD: Chief of Neonatology and Newborn Service, Children’s Hospital of PhiladelphiaJohn Heon, PhD: Professor of English and Writing, College of Arts and SciencesMark Pauly, PhD: Bendheim Professor of Healthcare Management, The Wharton SchoolPhilip Rea, PhD: Professor of Biology, College of Arts and SciencesHarvey Rubin, MD, PhD: Professor of Medicine, Penn School of MedicineBen Friedman: Third Year Medical Student, Penn School of Medicine

MANY THANKS TOSAC, PubCo, Kaplan, The New York Times, Georgette Phillips, Daniel Cosgrove, Rochelle Bagatell, Peter Adamson, Sherman Stein, Emma Alden, Andrew Rech, Andrew Coopersmith, Elise Dihlmann-Malzer, and Meera Ragavan

THE EXECUTIVE BOARD

BACK: Nicholas Wilcox Joshua Sherman, Cary Kraft, Amit Saha, Anand GopalFRONT: Diana Lu, Jaclyn Chen, Elizabeth Saionz

Business StaffKaushik AnnamAndre BorczukQinnan LinLauren Wilcox

Copy StaffDara BakarShabnam ElahiEmily LinBrandon Mustin

Design StaffBillie BianAshley Wu


INNOVATIONS IN ROBOTIC SURGERY 18The da Vinci robotic system as a breakthrough in surgical care.

BRAIN TRAUMA 22Evaluating the effectiveness of decompressive craniectomy

ORGAN TRANSPLANTATION 20Alternative treatments that address shortcoming in traditional immunosuppressive therapies.

A GIFT OF VOICE 24Modern surgical techniques for laryngeal transplantation

spring 2011CONTENTS

COMPASSIONATE CANCER CARE 10Insights into pediatric oncology at the Children’s Hospital of Philadelphia

SOCIE-ECONOMIC HEALTH DISPARITIES 4Evaluating healthcare programs in underserved populations

CHOLERA IN HAITI 8A case study addressing cholera in the developing world

WEST PHILADELPHIA OBESITY EPIDEMIC 5Analyzing community-based obesity health initiatives

THE PHYSICIAN PATIENTRELATIONSHIP 13The importance of effective communication for patient care

policy

THE MD/PHD 16The role of the physician researcher in enhancing clinical care

LANGUAGE BARRIERS IN MEDICINE 14Solutions to alleviate miscommunication in patient care settings.

PHARMACEUTICAL ALLERGY CURE 26Exploring potent alternative treatments to common allergies

DETECTING DIABETES 27Analyzing the unique properties of non-enzymatic glucose sensors

INNOVATIVE GENETIC DIAGNOSTICS 30Genetic techniques to identify pre-natal birth defects

PHARMACEUTICAL SKUNKWORKS 32Reorganizing the pharmaceutical industry to spur innovation

clinical features research

For more SYNAPSE, visit our website: www.upennsynapse.com


HEALTHCARE POLICY

SOCIO-ECONOMIC STATUS AND URBAN HEALTH Ever since the development of urban areas, there has been a search to understand the relationship between health and the city. One of the key distinguishing elements that influence the condition of city life is the difference in socioeconomic status between residents (1). Socioeconomic status (SES) is defined as an individual’s place within the social structure, assessed by factors such as education, occupation, income and wealth (2). Thus, a thorough understanding of urban health conditions can be reached by evaluating the influence of low-socioeconomic status on two critical components of health: environmental exposure and health care access. Both components are directly related to an individual’s SES. As SES comprises important social factors such as education and income, it is critical to gaining a better understanding of the complexities of urban heath care.

HEALTH AND THE ENVIRONMENTIt has been shown that significant environmental factors impact the health of low SES individuals. These individuals often live in poor and dangerous environments, many times located near industrial zones, highways, or toxic waste sites, frequently due

to a lack of affordable alternatives. Most notably, in Detroit, almost 30% of the residents living less than two miles away from commercial hazardous waste facilities are below the federal poverty line.

(3) Thus, low SES individuals have greater exposure to damaging agents such as carbon dioxide, lead, and industrial wastes. (4) These sub-prime locations also experience worse air quality as a result of city and industrial pollution. Studies have shown that ambient air pollutants such as ozone found in photochemical smog can cause respiratory conditions and psychological issues. (5) For example, in a study evaluating the severity of asthma in children, 40% of the children in the low SES group reported severe asthma compared to the 16% in the high SES group. (6) In addition, respiratory health is exacerbated by the presence of molds and allergens in the housing units of low SES neighborhoods, which are consequences of the low-quality housing available in polluted areas. Furthermore, these residential areas are often crowded with residents living in close proximity to one another. The negative

health effects of close-quarter living in high population density SES urban areas are compounded by the poor quality of low SES housing. In New York City, the average low-income neighborhood has 17 square yards of park space per child compared to the typical high SES NYC neighborhood that has three times that amount. (4) Additionally, saturated communities function as a stressor, increasing neuroendocrine and blood pressure levels. (7) Ultimately, the confluence of these environmental factors contributes to the worse health low SES individuals.

DISPARITIES IN ACCESS AND THE PPACAAnother SES-related health disparity is limited access to healthcare. Healthcare services often are not available or improperly utilized. Compounding this is the fact that low-income patients usually present with multiple physical, social, and psychological problems, unlike high-income patients in suburban areas which have specific problems. (4) The presentation of multiple health problems causes administering health services in these areas to be more clinically challenging for physicians (4). Today, safety-net providers, not-for-profit organizations, and hospital outpatient clinics provide the majority of health care utilized by urban poor communities. (8,9) Although these agencies have significantly impacted urban health, they still face various challenges. (1) These health centers, often financially limited, have low physician retention rates, and lack resources to provide a wide range of services. The Affordable Care Act (PPACA) passed in 2010 has specific provisions to direct more resources to community-based health centers that often serve underserved and low income populations. These include new investments in community health teams as part of an effort to provide coordinated care, which are estimated to double the number of patients that health centers can serve (16). In addition, new funds will be made available for home visits for expectant mothers, which will help to address the higher infant mortality present in minority groups (16). Furthermore, the communication between providers and minority patients will be strengthened by requiring health plans to use language services and community outreach in underserved, minority communities (16). Currently, low-income patients are often uninsured, and 60% of the uninsured are from low-income families. This often means they are not able to receive the special services that they need (4,7). Through the recent health reform law, Medicaid eligibility will be significantly expanded to include all persons at or below 133% of the federal poverty line, which will provide universal access to health insurance for low-income individuals. PPACA has several revenue generating provisions that aim to finance these

Socioeconomic Status and the Future of Public Health Strategies

BY SHABNAM ELAHI

In order to better understand city health, one needs to first understand the city and the underlying socioeconomic hierarchy


investments. These include an expansion of the Medicare tax base for high-income individuals, a 40% tax on Cadillac health insurance plans, and an annual fee imposed on health insurance providers (17).

THE ISSUE OF UTILIZATIONAnother factor that influences health disparities is utilization of available health facilities in low SES areas. Even in countries that provide universal health coverage such as Canada, there are still distinct health disparities between the socioeconomic classes. Furthermore, despite universal coverage, those with low income and poor education are less likely to visit a specialist compared to those with higher income and education. (10,11) In the U.S., Medicaid and Medicare provide coverage for the poor and elderly, respectively. However, despite the availability of these programs, a substantial number of eligible individuals simply fail to apply (4). It is clear that even with the presence of these services, individuals of lower income and education may not take advantage of the opportunities. Arguably, this could undermine the effectiveness of PPACA in improving health for low-income populations by increasing access through Medicaid eligibility expansion. However, by supplementing universal healthcare coverage with specific initiatives to connect with low-income minority groups, as well as increased funding for community health centers that serve these populations, it may be possible to address underutilization of preventive services. Clearly, information about opportunities must be made available to low-income populations to raise awareness about healthcare benefits for which they are eligible.

COMBATTING HEALTH DISPARITIES: SPECIFIC URBAN AND COMMUNITY-BASED INITIATIVESOne city that has taken initiative to address health problems among the lower socioeconomic groups is New York City. A particular health issue that the city has been dealing is the increasing rates of obesity. In the city, 57% of adults and 39% of children are considered obese, and many of these overweight individuals live in poor neighborhoods (8). In response, the City Department of Public Health has put in place regulations to ban the sale of foods in city restaurants with .5 or more grams of trans fat. The ban was considered a success—use of trans fats in restaurants decreased from 50% to less than 2% in three years without impacting restaurants’ business performance, and this progress has paved the way for similar policies in other major cities such as Philadelphia, Seattle, and Baltimore (12). High obesity rates are also associated with the higher cost of healthy foods and the presence of cheap, sugar-laden snacks in low SES communities (7). The Department of Public Health plans to address these issues through the “Take Care New York 2012” health policy. The program aims to increase the availability of healthy foods in low-SES neighborhoods and to provide health education to New Yorkers. As the Take Care New York 2012 program has only just begun, the amount of progress made so far is not yet clear (8). The efforts taken by New York City to address the socioeconomic determinants of obesity only reflect part of a much larger discussion about policy. Some critics have suggested that obesity rates can be lowered in these regions by placing zoning restrictions on the number of fast food restaurants and repurposing the land for green spaces such as parks and bike trails. Additional proposals include decreasing the number of fast food commercials during children’s programs and incorporating health education classes into the curriculum

of schools. Furthermore, some argue for the implementation of tax on unhealthy foods so that healthy food purchases are incentivized. Even a 1-cent tax on all 12 oz. soft drinks would create $1.5 billion in annual revenue, and this money could be utilized to promote other health initiatives (13). Citywide projects can be effective in addressing the SES health gap, but so can community-based approaches outside of densely urban areas such as New York City. One such intervention to combat obesity was implemented by the El Rio Santa Cruz Community Health Center in Tucson, Arizona as part of the National Cooperative Inner-City Asthma Study (NCICAS). The program focused on initiating community based assistance with low-income city children with moderate to severe asthma. Consequently, there was a significant reduction in asthma symptoms, hospitalizations, and unscheduled primary care visits over a two week period (14). Moreover, the Bootheel Heart Health Project focused on improving cardiovascular health in the rural Bootheel region of southeastern Missouri. The project helped to fund aerobic exercise clubs, cardiovascular disease education classes, healthy cooking programs, and blood pressure, diabetes and cholesterol screenings. Most importantly, the project inspired community involvement. The local paper devoted a column to heart health, and community ministers discussed heart disease during their sermons on “High Blood Pressure Sunday.” Over the course of the study, the increase in physical activity and heart disease education led to reductions in cardiovascular disease risk in the area (15).

SUMMARYWith the passage of the new healthcare bill, there has been much attention given to improving the level of health across the country. Despite a national effort, so far the status of urban health has remained poor and unmoved. In order to better comprehend city health one needs to first cultivate an understanding of the city and the underlying socioeconomic hierarchy, an understanding that is integral to an effective approach to city health.

References

1 Galea, S, Freudenberg, N, & Vlahov, D. (2005). Cities and population health. Social Science and Medicine, 60, 1017-1033.

2 Alder, N, Boyce, T, Chesney, M, Cohen, S, & Folkman, S. (1994). Socioeconomic status and health: the challenge of the gradient. American Psychologist, 49(1), 15-24.

3 Evans, G, & Kantrowitz, E. (2002). Socioeconomic status and health: the potential role of environmental risk exposure. Annual Review Public Health, 23, 303-331.

4 Alder, N, & Newman, K. (2002). Socioeconomic disparities in health: pathways and policies. Health Affairs, 21(2), 60-76.

5 Eggleston, Peyton, Buckley, Timothy, Breysse, Patrick, Wills-Karp, Marsha, & Kleeberger, Jouni. (1999). The environment and asthma in u.s. inner cities. Environmental Health Perspectives, 107, 439-450.

6 Mielck, A, Reitmeir, P, & Wjst, M. (1996). severity of childhood asthma by socioeconomic status. International Journal of Epidemiology, 25(2), 388-393

7 N.E. Adler et al., “Socioeconomic Inequalities in Health: No Easy Solution,” Journal of the American Medical Association 269, no. 24 (1993): 3140–3145.

8 Summers, C., Cohen, L., Havusha, A., Sliger, F., & Farley, T. New York City Department of Health and Mental Hygiene, (2009). Take care new york 2012: a policy for a healthier new york city.

9 Fiscella, K, & Williams, D. (2004). Health disparities based on socioeconomic inequities: implications for urban health care. Journal of the Association of American Medical Colleges, 79(12), 1139-1147.

10 S. Dunlop, P. Coyte, and W. McIsaac, “Socio-Economic Status and the Utilization of Physicians’ Services: Results from the Canadian National Population Health Survey,” Social Science and Medicine 51, no. 1 (2000): 123–133.

11 Galea, S., & Vlahov, D. (2005). Urban health: evidence, challenges, and directions. Annual Review of Public Health, 26, 341-365.

12 Gosdin, L. (2007). Law as a tool to facilitate healthier lifestyles and prevent obesity. The Journal of the American Medical Association, 297(1), 89-90.

13 United States. Inner City Asthma. Aiken: , 2004. Web. 14 Feb 2011. <http://www.cdc.gov/asthma/interventions/inner_city_asthma_researchbase.htm>.

14 Bowson, Ross, Carol Smith, Michael Pratt, and Nilsa Mack. “Preventing Cardiovascular Disease through Community-Based Risk Reduction: The Bootheel Heart Health Project.” American Journal of Public Health 86.2 (1996): 206-213. Web. 14 Feb 2011. <http://ajph.aphapublications.org/cgi/reprint/86/2/206>.


Philadelphia, rates in West Philadelphia are particularly high.6 A study of the West Philadelphia population shows that adolescent obesity increased nearly four-fold over the last two decades; in one particular neighborhood, half of all children ages 6 to 17 are overweight or obese.6,7 These statistics are more alarming because they expose severe racial disparities. Disease prevalence is notably higher among African Americans than among whites. Therefore, communities like West Philadelphia, where 72% of the population is non-Hispanic black, bear a disproportionate amount of the disease burden.8

Obesity and being diagnosed as overweight can be attributed to a number of factors. While energy balance, or caloric intake, plays a critical role, obesity is inextricably linked to behavioral and environmental factors. One significant indicator is a sedentary lifestyle. The increased intake of high-energy foods coupled with low levels of physical activity increases the risk of overweight and obesity. Studies have indeed found low levels of physical activity among West Philadelphia children and adolescents.6 Furthermore, analyses of dietary intake among middle school students in West Philadelphia have shown that consumption of total fat, saturated protein, and carbohydrates exceeds recommended daily allowances and is higher than the national average for this age group.8 Lack of access to healthy food is another significant factor contributing to obesity. As nutrient-poor, high calorie foods have become cheaper and readily available, nutritious foods have become relatively more expensive. This trend increases the risk of excessive caloric intake among low-income populations – making the West Philadelphia population particularly susceptible to obesity. In Philadelphia, fruit and vegetable consumption is minimal, with nearly 25% of children and 30% of adults eating one or fewer servings per day. At the

same time, inexpensive sugar-sweetened beverages like soda and fruit drinks account for nearly two hundred extra calories for the average Philadelphian each day.3 Consumers in Philadelphia are not necessarily at fault for their insufficient intake of healthy foods. Particular areas that lack access to healthy food in grocery stores or markets are now labeled as “food deserts.” West Philadelphia, where obesity rates are disproportionately high, is among these “food deserts” that have few options when it comes to consuming healthy foods. Access and affordability therefore represent major barriers to maintaining a healthy diet and contribute to high obesity rates in Philadelphia. IMPROVING ACCESS TO HEALTHIER FOODSThe outlook is not all bleak: many people across the nation have taken note of the growing obesity crisis and lack of accessibility to healthy food, and are making moves to combat the problems. First Lady Michelle Obama started the major initiative “Let’s Move”, which is focused on childhood obesity prevention. Shortly after her program’s successful launch, Mrs. Obama came to Philadelphia to highlight one pillar of the program: access to healthy, affordable food. Along with the Treasury Secretary and USDA Secretary, the First Lady made local stops to showcase the widespread problem of “food deserts” and how Philadelphia has recently taken steps to bring healthier food to its communities.9

Private businesses have also made an effort to promote healthier lifestyles. The Fresh Grocer supermarket chain aims to provide access to quality groceries in urban locations often ignored by other popular chains and in July 2009 operated 8 stores in Philadelphia, with 2 more opening by the end of that year. In addition to providing low-income individuals with increased access to healthier foods, the company has also made efforts to increase awareness

Making Moves to Address Childhood and Adolescent Obesity in Philadelphia

BY GABRIELA ABRISHAMIAN-GARCIA

In the late 1990s, pediatricians at the Children’s Hospital of Philadelphia began to notice an alarming trend among their patients— an increasing numbers of patients were diagnosed with Type 2 diabetes mellitus, which was previously so rare among children that it was called “adult-onset” diabetes. The disease is usually found in people older than 40 years, but is increasing in incidence among overweight children and adolescents in Philadelphia and nationwide.1 Doctors estimate that half of overweight kids will grow up to be overweight adults. Many will be on disability insurance and will require treatment for various obesity-related conditions—diabetes, cardiovascular disease, hypertension, stroke, and certain forms of cancer—for the rest of their lives.2 In addition to its damaging health consequences, obesity has high economic costs. According to a study of national costs attributed to both overweight and obesity, expenditures have reached as high as $147 billion in 2008.3 These enormous health costs for individuals and society have also nearly doubled in the past decade and will continue to rise as the epidemic intensifies.4 Individuals, health organizations and the government are beginning to take action to curb the obesity epidemic, especially in areas that need it the most.

THE PHILADELPHIA OBESITY CRISISPhiladelphia currently has the highest obesity rate of the nation’s ten largest cities.5 In 2008, 64% of adults were classified as overweight or obese. Since 2000, approximately 24,000 Philadelphians have died of diseases caused by poor diet and physical inactivity.3 These high rates have heightened public health concerns and have drawn significant attention to the growing rates of childhood obesity in particular. While 17% of children and adolescents are obese in the city of


References

1 “Diabetes Tops Child Obesity’s Health Risks.” Main Line Health . N.p., n.d. Web. 14 Feb. 2011. <http://www.mainlinehealth.org/stw/Page.asp?PageID=STW000987>.

2 Controlling the Obesity Epidemic. World Health Organization. Retrieved February 7, 2011, from www.who.int/nutrition/topics/obesity/en/index.html.

3 Obesity in Philadelphia (2010). Philadelphia Department of Public Health

4 Obesity and Overweight for Professionals: Data and Statistics: U.S. Obesity Trends. (n.d.). Centers for Disease Control and Prevention. Retrieved February 6, 2011, from http://www.cdc.gov/obesity/data/trends.html

5 Bayliss, K. (n.d.). Fat in Philadelphia. NBC Philadelphia. Retrieved February 7, 2011, from http://www.nbcphiladelphia.com/news/local-beat/Fat-in-Philadelphia-90082062.html

6 Gordon-Larsen, P. (2001). Obesity-related knowledge, attitudes, and behaviors in obese and non-obese urban Philadelphia female adolescents. Obesity Research, 9, 112-118.

7 Faison, H. (2010, September 27). How a West Philadelphia family overcame child obesity. Philadelphia Inquirer. Retrieved February 7, 2011, from http://www.philly.com/philly/health_and_science/20100927_How_a_West_Philadelphia_family_overcame_child_obesity.html

8 Johnston, Francis E., and Ira Richard Harkavy. The obesity culture: strategies for change : public health and university-community partnerships. St Ives, UK: Smith-Gordon, 2009. Print.

9 Bryan, C. (2010, February 18). Michelle Obama tackles ‘food deserts’ in Philadelphia . Examiner.com. Retrieved February 7, 2011, from http://www.examiner.com/michelle-obama-in-national/michelle-obama-tackles-food-deserts-philadelphia

10 (2009, July 1). Fresh Grocer Hosts Free Health Fair.Progressive Grocer. Retrieved March 25, 2011, from http://www.progressivegrocer.com/top-stories/headlines/snacks/id19171/fresh-grocer-hosts-free-health-fair/

11 Lattanzio, V. (2010, May 14). Property Taxes UP, Soda Tax Out in Philly. NBC Philadelphia. Retrieved February 7, 2011, from http://www.nbcphiladelphia.com/news/politics/Property-Taxes-Soar-Soda-Tax-Out-in-Philly-Budget-93734699.html

12 Elbel, B., Gyamfi, J., Kersh, R. (2011). Child and adolescent fast-food choice and the influence of calorie labeling: a natural experiment. International Journal of Obesity, Ahead of print, 1-8.

13 U.S. Department of Agriculture, Food and Nutrition Service (2005, March). Making It Happen! School Nutrition Success Stories. USDA. Retrieved March 25, 2011, from http://www.fns.usda.gov/tn/Resources/makingithappen.html

14 Melnyk, B., Small, L., Morrison-Beedy, D., Strasser, A., Spath, L., Kreipe, R., et al. (2007). The COPE Healthy Lifestyles TEEN Program: Feasibility, Preliminary Efficacy, & Lessons Learned from an After School Group Intervention with Overweight Adolescents. Journal of Pediatric Health Care, 21(5), 315-322.

15 Urban Nutrition Initiative. AUNI - Agatston Urban Nutrition Initiative . Retrieved February 7, 2011, from http://www.urbannutrition.org/

16 Students Run Philly Style. Students Run Philly Style. Retrieved February 7, 2011, from http://www.studentsrunphilly.org/about.html

17 Our History | SRLA. (n.d.). Students Run LA. Retrieved March 25, 2011, from http://srla.org/about-us/our-history/

about healthy living; for example, one Fresh Grocer in Philadelphia hosted a free health fair in June 2009 that witnessed a successful turnout in the hundreds.10

The Philadelphia legislature has also pushed to implement measures to address this major public health concern. Last year, Mayor Nutter proposed a two-cent tax per ounce on all soda and sugary drinks sold within the city limits. While some commended the measure, it ultimately faced strong opposition and was not approved in the city’s budget. However, Philadelphia did begin to enforce menu-labeling law—the strictest in the nation—that requires restaurant chains to list calories on food tags and menu boards. The idea is that by reading calorie and fat content, Philadelphians will be able to make educated decisions on what they are consuming, allowing them to make healthier choices.11 Although research conducted in New York and Newark did not find any reliable difference in fast food purchases before or after labeling foods, Philadelphia’s policy was implemented only recently, and so critics may have to wait some time to see how it affects this particular city’s health.12

LOCAL INITIATIVES TO IMPROVE CHILD AND ADOLESCENT HEALTHWhile national programs and policies may improve access to healthy foods, local initiatives that promote lifestyle changes through healthy eating and exercise may be the most effective and enduring measures in the fight against obesity. At the educational level, numerous schools have worked to improve student activity and diet and have seen a number of health benefits, including helping students lose weight and improving academic performance.13, 14

The Urban Nutrition Initiative (UNI) is one organization that aims to positively address the childhood and adolescent obesity epidemic. UNI is a university-community partnership based at the University of Pennsylvania that engages children ages 5-16+ in “an active, real-world problem-solving curriculum that strives to improve community nutrition and wellness”.15 UNI organizes programs in West Philadelphia schools including cooking clubs, gardens, student-run fruit stands, and even after-school family exercise classes. These programs empower students to take control of their health, and their family’s health, in a stimulating, collaborative and sustainable way.15

Students Run Philly Style is another local initiative that has made an impact in promoting healthy lifestyles among Philadelphia youth. The organization addresses high obesity rates among children by offering marathon training. Students are paired with adult mentors who help them set and accomplish goals, ultimately to complete an entire marathon, encouraging them to become life-long athletes. The program aims to provide participants with significant life and health benefits and a safe after-school environment based on the success of the similar program Students Run LA, which in 20 years has seen over 95% of its participants complete the Los Angeles marathon and over 90% go on to attend college.16, 17

Efforts such as these may not provide immediate results in reducing the prevalence of obesity, but will undoubtedly have a long-term effect. If students learn and are encouraged to make better decisions about what to eat and how to stay active, they can bring this knowledge into their homes, where most dietary and lifestyle habits are reinforced.

STEPS IN THE RIGHT DIRECTIONIt may seem be difficult to stay optimistic about the impact of nutrition-promoting initiatives as the obesity epidemic continue to burden Philadelphia, the U.S and even the world. However, various nutrition initiatives have the potential to make a significant difference. By educating people, especially children and teens, about the risks of obesity and the importance of healthy eating and exercise, these programs could gradually encourage healthy lifestyles and reduce the incidence of disease. The changes that children make to their health habits improve their current and future health, and can also inspire those around them to make positive changes. The ten-year old child diagnosed with Type 2 diabetes will lose weight and adopt healthier eating habits while training for a marathon with a Students Run Philly Style mentor. The teenager from a West Philadelphia middle school will take home the healthy snacks she buys at the school fruit stand run by UNI. The mother with her young child may opt for a healthier meal option after checking the available nutritional information. These initiatives in Philadelphia and across the nation represent critical steps towards promoting individuals and their families to live longer, happier, and healthier lives.

“The Agriculture Department wants to change the content of federally subsidized school meals—33 million lunches and 9 million breakfasts a day—by the fall of 2012. Beyond the calorie cap, the new standards would emphasize whole grains, vegetables and fruits and set tighter limits on sodium and fats.” — New York Times


Buildings collapsed atop rubble, meandering rivers littered with feces, and millions of people destitute, hungry and homeless—the devastating aftermath was clearly evident. On January 12, 2010, a magnitude 7.0 earthquake struck Haiti, with an epicenter approximately 15 miles west of its capital Port-au-Prince.1

With more than 80% of its 9.7 million people living below the poverty line prior to the earthquake, Haiti was already the poorest country in the western hemisphere.2,3 Now, this economically downtrodden nation must also overcome the lingering aftermath of a destructive earthquake. The rainy weather, lack of clean water and fields of makeshift encampments had turned the country into a flooded cesspool. Many healthcare professionals feared the spread of infectious diseases such as malaria, dengue and typhoid.4 One disease missing from these checklists, however, was cholera.

THE ONSET OF CHOLERA IN HAITICholera is a potentially fatal intestinal infection caused by the gram-negative bacteria Vibrio cholerae.5 Symptoms include severe diarrhea and vomiting, which if left untreated, will often lead to death by dehydration and electrolyte imbalance. Scientists had good reason to believe an epidemic in Haiti was unlikely; the last Haitian outbreak had occurred more than a century ago and the pathogen had been noticeably absent since then.6,7 This absence existed in spite of poor sanitary conditions, which were present before the earthquake. In fact, only 17% of Haitians have access to improved sanitation facilities,8 which the World Health Organization (WHO) defines as facilities that “ensure hygienic separation of human excreta from human contact”.9 Fecal contamination, which can subsequently lead to diarrheal disease, was a major cause of childhood deaths during the last outbreak.8

On October 21, 2010, Haiti’s Ministry of Public Health and Population (MSPP) confirmed the cholera outbreak, with a majority of cases centered in rural Artibonite, 62 miles north of the capital.10 Despite escaping the quake’s devastations, the town was now burdened by the countless encampments of homeless refugees. By the end of December 2010, the disease killed 3,600 Haitians, while seriously affecting 170,000 more.8 While there are no official confirmations of the reintroduced pathogen’s source, this particularly virulent strain may have originated from foreign aid workers who arrived following the earthquake. Regardless of its time of arrival, the bacteria’s robust survival and epidemic development certainly exacerbated health conditions resulting from the earthquake. Following DNA sequencing, the Centers for Disease Control and Prevention (CDC) identified the strain to be Vibrio cholerae serotype O1, biotype El Tor, the same strain endemic to South Asia.5

INFECTION, TREATMENT, AND PREVENTION The most common form of cholera transmission is through contaminated food and water, in which the bacteria can survive

several months depending on pollutant content.11 Various strains of V. cholerae, including historically epidemic—and pandemic-causing serotypes O1 and O139, are unique in their ability to survive the acidity of the stomach.5 Following gastric passage, the bacteria colonize by attaching to the mucosa lining of the small intestine. Rapid pathogenic proliferation and subsequent cholera toxin secretion leads to diarrhea, forcing the body to expel large amounts of water—along with the infecting pathogen’s progeny—out of the body.5 This survival mechanism often leads to dangerous rates of water loss, with some adults losing between half to one liter an hour.5 While incubation time varies from 18 hours to 5 days, death can ensue within hours of symptomatic onset.5 Severe dehydration also leads to secondary symptoms such as low blood pressure, rapid heart rate, poor skin turgor, wrinkled hands and feet, no urine output, severe muscle cramps, and miscarriage or premature delivery by pregnant women.5 Current treatments include oral rehydration salts for moderate severity and intravenous solution of Ringer’s solution (an aqueous solution of salts) for the most severe patients. Both fluids correct for metabolic acidosis and potassium deficiency, as well as general fluid replacement.5 An oral antibiotic such as doxycycline can also be taken after vomiting has stopped, which will speed the recovery process.5 Antibiotics, however, should not be used as prophylactics due to increased risk of developing antibiotic resistance.5

Two oral vaccines are currently marketed: Dukoral, consisting of killed V. cholerae and cholera B subunit, which is touted to induce both antitoxic and antibacterial immunity; and Orochol, a genetically modified avirulent mutant of the infecting bacteria. 5Major impediments to the successful implementation of these vaccines include short efficacy time period, relatively low protection rates, and difficulties in mass distribution.

CURRENT RESEARCH AT PENNThe persistence of V. cholerae has led to increased interest in the pathogen’s survival mechanisms. These bacteria live in nearly all aquatic ecosystems, including marine, freshwater and estuarine.12 These coccoid bacteria form specialized multicellular communities called biofilms, whose highly organized structure provide increased environmental stress resistance.13 Research shows that while the bacteria are not directly culturable in biofilm form, the O1 serotype remains virulent upon animal passage.14,15 Strains capable of biofilm formation have demonstrated significantly higher pathogenicity, which inherently leads to natural selection, resulting in increasingly virulent outbreaks.14

Members of Dr. Jay Zhu’s laboratory in the Department of Microbiology of the University of Pennsylvania primarily study the bacteria’s quorum sensing pathway, especially with relevance to biofilm formation and pathogenesis. Quorum-sensing is a mechanism often utilized by gram-negative bacteria to ensure that sufficient cell numbers are present to produce virulency. In general, this signal transduction pathway often leads to suppressed

Lessons from Haiti:Combating Cholera in Developing Nations

BY BILLIE BIAN


expression of the virulence gene.16 The researchers were able to demonstrate the negative regulation of V. cholerae biofilm formation and architecture by the quorum sensing pathway’s hapR repressor, whose expression is induced in high-density cell populations. Increased levels of hapR and CAI-1, a quorum-sensing signal molecule, confirmed these results. Timing of hapR expression was also crucial in determining biofilm thickness, as well as eventual colonization efficiency upon infection.12 By gaining a better understanding of the mechanisms governing the quorum-sensing pathway, researchers at Penn are shedding light on the processes underlying virulency in V. cholerae. Furthermore, researchers have discovered that AHL lactonase, a protein isolated from several Bacillus species, could significantly reduce V. cholerae’s ability to form biofilms.17 This enzyme could mitigate the bacteria’s ability to survive in unfavorable conditions, thereby lessening its chances of spreading. Andrew Stern, a third year MD-PhD candidate in Dr. Zhu’s lab, admits that the goal of his research, however, is not to develop a drug or vaccine for cholera, since the treatments available today work sufficiently well. Rather, his research group at Penn aims to understand the infection pathways modeled by V. cholerae, to elucidate how the body and pathogen are manipulated throughout the infection process, and to apply this knowledge to other infectious models. Nevertheless, Stern remains hopeful: “Perhaps this will lead to more effective antibiotics. Perhaps we’ll find some factor that allows vibrio cholerae to cause an epidemic,” said Stern. “Perhaps we don’t know everything.” As a member of the only lab at the University researching V. cholerae, Stern admits, with good reason, that today’s research interests are not necessarily focused on the bacteria alone, but rather its application. “We have treatments. And they’re really good,” said Stern. “It’s really a problem of access to clean water.”

BARRIERS TO INCREASING ACCESS: A GLOBAL PERSPECTIVECholera remains endemic to many of the poorest parts of the world, including Sub-Saharan Africa, India, and Bangladesh. It is estimated to kill between 100,000-120,000 people each year, and affects an estimated 3-5 million more.18

The barrier to eradicating cholera does not relate to developing better medical treatments; existing medications are effective. Rather, the main barrier is a public health one—the lack of proper sanitation in developing countries. This includes installing latrines where defecated material cannot easily contaminate the local drinking water. There is a significant unmet need to install filtration systems and integrate basic sanitation measures such as hand washing into the educational systems of countries such as Haiti. Complete control of cholera requires extensive infrastructural development, in which municipalities and rural water systems separate drinking and wastewater. Without such improvements—in both facilities and education—cholera will remain endemic. Given the generous aid following the earthquake, such improvements—with significant organization and planning—may be possible in Haiti. But assistance must also be given to other at-risk countries as well. Without addressing sanitation, the bacteria will continue to live and spread, affecting the most vulnerable countries when the opportunity presents itself.

References

1 Magnitude 7.0 - HAITI REGION. (n.d.). U.S. Geological Survey Earthquake Hazards Program. Retrieved February 10, 2011, from http://earthquake.usgs.gov/earthquakes/recenteqsww/Quakes/us2010rja6.php

2 Haiti - The World Fact Book. (n.d.). Central Intelligence Agency. Retrieved February 9, 2011, from https://www.cia.gov/library/publications/the-world-factbook/geos/countrytemplate_ha.html

3 UN-OHRLLS :: Haiti. (n.d.). UN-OHRLLS - Home Page. Retrieved February 10, 2011, from http://www.unohrlls.org/en/orphan/92/

4 Bayard, D. (2010). Haiti Earthquake Relief, Phase Two - Long Term Needs and Local Resources. New England Journal of Medicine, 362(20), 1858-1861.

5 Sack, D. A., Sack, R. B., Nair, G. B., & Siddique, A. K. (2004). Cholera. The Lancet, 363(January 17, 2004), 223-233.

6 Cholera in Haiti | CDC Travelers’ Health. (n.d.). Centers for Disease Control and Prevention. Retrieved February 8, 2011, from http://wwwnc.cdc.gov/travel/content/id/2487.aspx

7 CDC - 2010 Haiti Cholera Outbreak: Cholera Confirmed in Haiti. (n.d.). Centers for Disease Control and Prevention. Retrieved February 8, 2011, from http://www.cdc.gov/haiticholera/situation/

8 Dowell, S. F., Tappero, J. W., & Frieden, T. R. (2011). Public Health in Haiti — Challenges and Progress. New England Journal of Medicine, 364(4), 300-301.

9 Progress on sanitation and drinking-water 2010 update. (n.d.). Water Sanitation and Health (WSH) . Retrieved February 10, 2011, from www.who.int/water_sanitation_health/publications/9789241563956/en/index.html

10 Ministry of Public Health and Population, Haiti. Pan American Health Organization. CDC. (2010). Cholera Outbreak – Haiti, October 2010. Morbidity & Mortality Weekly Report. 59(43), 1411.

11 Pandit, C. G., Pal, S. C., Murti, G. V., Misra, B. S., Murty, D. K., & Shrivastav, J. B. (1967). Survival of Vibrio cholerae Biotype El Tor in Well Water. Bulletin of the World Health Organization , 37(4), 681-685.

12 Liu, Z., Stirling, F. R., & Zhu, J. (2007). Temporal Quorum-Sensing Induction Regulates Vibrio cholerae Biofilm Architecture. Infection and Immunity, 75(1), 122-126.

13 Heithoff, D. M., & Mahan, M. J. (2004). Vibrio cholerae Biofilms: Stuck between a Rock and a Hard Place . Journal of Bacteriology, 186(15), 4835-4837.

14 Alam, M., Sultana, M., Grim, C. J., Huq, A., Colwell, R. R., Nair, G. B., et al. (2007). Viable but nonculturable Vibrio cholerae O1 in biofilms in the aquatic environment and their role in cholera transmission . Proceedings of the National Academy of Sciences, 104(45), 17801-17806.

15 Molloy, S. (2007). Environmental microbiology: Biofilms in the time of cholera. Nature Reviews Microbiology, 5(12), 906-907.

16 Cámara, M., Hardman, A., Williams, P., & Milton, D. (2002). Quorum sensing in Vibrio cholerae. Nature Genetics, 32, 217-218.

17 Augustine, N., Kumar, P., & Thomas, S. (2010). Inhibition of Vibrio cholerae biofilm by AiiA enzyme produced from Bacillus spp. Archives of Microbiology, 192, 1019-1022.

18 Cholera. (n.d.). Cholera Key Facts. Retrieved February 8, 2011, from www.who.int/mediacentre/factsheets/fs107/en/index.html

In recognition of World Water Day, Penn’s School of Nursing, in association with the Xi Chapter of Sigma Theta Tau International, sponsored a 5km walk to raise money for the construction of a filtration system to provide clean water a nursing school in Port-au-Prince, Haiti.

World Water Day at Penn

ALEXANDRA TOBOLSKY / PHOTO


A Glimpse into the Life of Pediatric OncologistsTwo leading pediatric oncologists at CHOP provide insight into the emotional and physical stress inherent to their jobs, while reveling in the satisfaction they receive on a daily basis.

BY JOSH BELFER

FRONT FACE PIC OF DOCTOR

DR. ROCHELLE BAGATELL

FRONT FACE PIC OF DOC

DR. PETER ADAMSON

Watching a teenager take his last breaths. Telling a high schooler that her life is about to turn upside down. Consistently grappling with serious emotions that emerge only in life or death situations. Such is the job of a pediatric oncologist. Few are cut out to work in such a high stress, high stakes environment, but those who do often gain a sense of satisfaction and accomplishment that can rarely be matched in other fields. Interviews with two leading clinicians from The Children’s Hospital of Philadelphia have revealed interesting—and perhaps, surprising—insights into the emotional and professional trials and tribulations of pediatric oncologists. Meet two renowned physicians who are members of the Cancer Center at CHOP. Dr. Rochelle Bagatell is an assistant professor at the University of Pennsylvania School of Medicine who specializes in the care of children with solid tumors. Dr. Peter Adamson is a professor of pediatrics at the School of Medicine and also serves as the chair of the Children’s Oncology Group, a global, clinical cooperative group that brings together five thousand experts in childhood cancer.1 Drs. Bagatell and Adamson emphasized the fact that physicians must not only possess a wealth of knowledge about their field, but must also be skilled enough to convey that information to the patient and his or her family. A 2010 Swedish study conducted through interviews with ten oncologists, each with more than ten years of

experience in pediatric oncology, revealed that a primary goal of oncologists “working with seriously ill and dying children”2 is to obtain as much knowledge as possible about the specific condition. Dr. Adamson echoed this sentiment. He explained that, as families first become affected by cancer, one of their main concerns is that their doctor “knows his stuff.”3 Dr. Bagatell reinforced this point by identifying some of her biggest influences in medical school as “the sharpest, most rigorous thinking” individuals.4 Thus, a critical factor in the care of pediatric cancer patients is that the family feels assured that they are in good hands over the course of the cancer treatment. There may be no better way for physicians to establish this confidence than by effectively conveying their knowledge of the literature to the family. While clinical knowledge regarding disease manifestation is critical, pediatric oncologists must also possess the interpersonal skills to communicate difficult information in a straightforward but sensitive manner. Dr. Adamson insisted that one of the fundamental qualities needed by a physician in this field is to feel “comfortable working with children and families.”3 This skill is perhaps most crucial when a doctor provides the initial cancer diagnosis to the patient and his or her family. While professionalism is of the utmost importance, the mental anguish that comes with providing such life-changing news to a family is unavoidable. “The worst thing that you can do is be vague,” Dr. Bagatell stated. “I think that clarity from the

FRANCES HU / PHOTOS

CLINICAL


References

1 Oncology | The Children’s Hospital of Philadelphia. (n.d.).The Children’s Hospital of Philadelphia | The Children’s Hospital of Philadelphia. Retrieved February 15, 2011, from http://www.chop.edu/service/oncology/home.html

2 Stenmarker, M., Hallberg, U., Palmérus, K., & Márky, I. (2010). Being a messenger of life-threatening conditions: Experiences of pediatric oncologists. Pediatric Blood & Cancer, 55(3), 478-484.

3 P. Adamson, personal communication.

4 R. Bagatell, personal communication.

5 Slavin, L. A., O’Malley, J. E., Koocher, G. P., & Foster, D. J. (1982). Communication of the cancer diagnosis to pediatric patients: impact on long-term adjustment. The American Journal of Psychiatry, 139(2), 179-183.

LEFT: The Children’s Hospital of Philadelphia (CHOP) treats more children

with cancer than any other pediatric hospital in the nation, and is ranked second nationally by the U.S. News & World Report

in pediatric oncology.

RIGHT: The Reath Terrace of the Children’s Hospital of Philadelphia. The Cancer Center

at CHOP employs more than 40 pediatric oncologists, many of whom are leaders in

their field. In addition, CHOP cancer care is a world renowned center for treating

neuroblastoma, and it boasts the largest brain tumor center in the United States.

very beginning—being clear, being careful, choosing your words properly—those are the things I try to focus on in my first visit.”4

A 1982 study that surveyed over one hundred childhood cancer survivors supported the theory “that early knowledge of the cancer diagnosis is related to good psychosocial adjustment.”5 Pediatric oncologists like Dr. Bagatell recognize the importance of open and honest communication with the patient and the family from the moment of initial diagnosis. Many doctors in alternative fields would agree that a good relationship with the patient is necessary, but pediatric oncologists sometimes face the unique challenge of weighing their role as professionals against their role as a support system for their patients. While tending to patients under such emotionally demanding circumstances, pediatric oncologists are often asked for professional and personal advice by families. In response to presenting treatment options, these doctors frequently receive one question: “What would you do if it were your child?” Dr. Adamson resolutely believes that childhood cancer is a disease that “really strikes at the core of who you are as a human.”3 As a result, he recognizes the importance of answering the above question with honesty and acknowledges that, having never been placed in such a situation, “It’s truly beyond the realm of any parent’s imagination”3 to know how to proceed. Instead, Dr. Adamson guides parents based on his knowledge of childhood cancer, its treatment and his experience with families facing similar

choices. While Dr. Bagatell was in general agreement with Dr. Adamson’s premise, she explained that she tries “to use evidence-based medicine as much as [she] can,” and will tell the family that she would not offer a treatment she thought was unreasonable. In her words, she “carefully [tries] to offer a hand to help.”4 While no single right answer exists, the approaches that Drs. Adamson and Bagatell take in responding to this question are ones that are respectable and provide unique insight into the personal and professional balance that pediatric oncology necessitates. Behind all of the emotional stresses of the field, a point that was mentioned time and time again by the doctors was the satisfaction and fulfillment that pediatric oncologists receive from their jobs; both Drs. Adamson and Bagatell could not imagine themselves doing anything else. To a certain extent, pediatric oncologists feel a need to constantly challenge themselves, and this specialty certainly requires them to do so on a daily basis. Physicians in this field face many unique challenges, both on the personal and professional levels. Much more goes into the makeup of these doctors than merely the information taught in medical school, and the specialized role of doctors in this field is evident in their ability to handle such delicate emotions on a daily basis. While pediatric oncology can be an extremely taxing field, seeing firsthand “the real amazing stories [of families] who…find unbelievable strength”3 to persevere during the cancer experience provides immeasurable gratification.



One expects a doctor to be clinically capable of accurately identifying health problem and taking the requisite steps to treat it effectively. The doctor’s capacity to do this is strongly contingent upon more than just medical knowledge—it also depends on his or her ability to listen and communicate before and after patient consultations. However, statistics have indicated that many doctors have difficulty forming an effective connection with their patients. During consultation, doctors must collect a complete medical history in order to map out a full account of the patient’s symptoms. Studies show that patients were interrupted, on average, within 18 seconds after they begin speaking, and can only complete their statements 23% of the time.1 Furthermore, doctors are more likely to assume that the patient is following the treatment plan, without explicit verbal confirmation.1 Given that communication is of key importance to a patient’s health, researchers are developing innovative strategies to improve doctor-patient interactions during consultation sessions, many of which rely on Internet and e-health resources. Effective communication begins when the physician takes a patient’s medical history. While it may seem obvious that the best way to do this thoroughly is to allow a patient to fully explain his or her concerns, physicians are not always good at allowing this to happen. The resulting failure to collect a complete patient history is a primary cause of misdiagnosis.2 To combat this problem, researchers at the University of Oslo have proposed a value chain model for consultations. This model breaks the consultation down into several key steps and focuses on improving interactions at every stage.3 By establishing a rapport with the patient, listening to the patient’s concerns and expressing empathetic support, the doctor can conduct a comprehensive consultation that will leave both the doctor and patient more satisfied. The value chain model for medical consultations illustrates the important influence that interaction has on

BY OLIVIA BERNAL the outcome of the consultation.3 This model also reveals the importance of explicitly addressing the emotional feelings of a patient during a consultation. Establishing rapport has been linked with physiological synchrony in heart rate and mimicry, both of which facilitate mutual positivity in the interaction.3 Patients benefit from feeling at ease when voicing their concerns, especially if they sense the doctor is listening to them as people rather than a cluster of symptoms. Furthermore, patients benefit from their physician’s empathetic support.4 A consultation can be an emotionally trying experience for the patient, and thus their emotional well-being is as important as their physical health and should be carefully considered. In addition to processing information from a patient’s medical history, doctors must reconcile information that patients may have gathered on their own about their symptoms. A computer-literate patient base with the power to utilize a variety of online health resources presents new challenges to the medical community. Within these online resources, a MEDSTAT survey reported that most patients are searching for disease-specific information as well as general preventative health information.5 With so many available options, doctors will often deal with patients who arrive with a treatment plan in mind. Even worse, these doctors may experience difficulty when presenting a diagnosis to stubborn patients who rely on virtual advice. To solve this complication, communicating detailed reasons for diagnosis to the patient is essential. Studies show that patients trust that their doctors are capable of making the right decision.6 Patients also prefer to hear more, as opposed to less, information from their doctor on the condition of their health.7 In a study that observed emotionality and authority in clinical relationships, parents of children with leukemia expressed feeling comforted by their doctor’s exercise of authority when presenting a treatment plan.6

Email has paved the way for more involved communication with physicians. When asked if they believed email is a good communication tool, 85% of patients responded to the affirmative.8 Doctors at Penn State College of Medicine performed a study in which one sample of patients was given the option to communicate with their physician via email while the other was not. After six months

Improving the Quality of Patient-Physician Communication

A computer-literate patient base with the power to utilize a variety of online health resources presents new challenges to the medical community.

As many Penn students prepare to enter the healthcare industry, it will be our responsibility to integrate new methods of communication withtraditional methods.

FRANCES HU / PHOTO


A trip to the emergency department is always stressful. A pressing medical problem with an uncertain outcome can be truly frightening. If this is trying enough, imagine not being able to communicate your problems to the clinical staff. This was the case for an 18-year-old Hispanic boy with limited English proficiency, who initially told his girlfriend and her mother that he felt “intoxicado” (translation: nauseated). He then collapsed and was taken to the ER. When this information was relayed to the clinical staff, who did not have access to interpreting services, and so understood “intoxicado” to mean intoxicated. It wasn’t until the patient had spent 36 hours in the hospital for treatment of a drug overdose that the actual cause of his symptoms—several intracranial hematomas, which result a ruptured artery in the brain pooling blood—was properly diagnosed.1,2 The hematomas eventually caused compression of the pateint’s brain stem, and led to quadriplegia. Unfortunately, this outcome could have been prevented if the patient’s condition had been properly diagnosed and treated right away.1 In 2007, there were 22 million Americans with limited English proficiency. This number has risen from 19 million in 2000 and continues to grow. In 2000, 2.4 million school age children were reported to have limited English proficiency, a number that has increased 85% since 1979.3 People with limited English proficiency are at risk for language barriers. According to a Robert Wood Johnson Foundation report on language barriers in hospitals, “communication is essential to quality.”4

Language barriers can hinder patients from fully understanding the information they receive during appointments, causing shame and embarrassment, and interfering with the trust of the provider-patient relationships. Research shows that people with limited English proficiency are less likely to seek preventative healthcare services. This may occur for many reasons. “Persons with limited English… may not be able to communicate to the provider that they desire screening, or providers may not be able to discuss or offer screening in an effective way.”5 Immigrants and people with limited English proficiency may not be aware of the available health services or their

References

1 Roter, D. Frankel, R. (1992). Quantitative and qualitative approaches to the evaluation of the medical dialogue. Social Science & Medicine, 32, 1097-1103. Retrieved February 15, 2011 from the ScienceDirect database.

2 Hernandez, M. McDonald, C. Gofman, Y. (2010). Physician Familiarity with the Most Common Misdiagnoses: Implications for Clinical Practice and Continuing Medical Education. The Internet Journal of Medical Education 2010, 1, 2.

3 Finset, A. Mjaaland, T.A. (2008). The medical consultation viewed as a value chain: A neurobehavioral approach to emotion regulation in doctor-patient interaction. Patient Education and Counseling, 74, 323-330. Retrieved February 8, 2011 from the ScienceDirect database.

4 Shields, CG. Epstein, RM. Franks, P. (2005). Emotion language in primary care encounters: reliability and validity of an emotion word count coding system. Patient Education and Counseling, 57, 232-238.

5 Ball, M. Lillis, J. (2001). E-health: transforming the physician/patient relationship. International Journal of Medical Informatics, 61, 1-10. Retrieved February 9, 2011 from the ScienceDirect database.

6 Young, B. Ward, J. Forsey, M. Gravenhorst, K. (2010). Examining the validity of the unitary theory of clinical relationships: Comparison of observed and experienced parent-doctor interaction. Patient Education and Counseling, In Press. Retrieved February 9, 2011 from the ScienceDirect database.

7 Vick, S. Scott, A. (1998). Agency in health care. Examining patients’ preferences for attributes of the doctor-patient relationship. Journal of Health Economics, 17, 587-605. Retrieved February 7, 2011 from the ScienceDirect database.

8 Leong, S. Gingrich, D. Lewis, P. (2005). Enhancing Doctor-Patient Communication Using Email: A Pilot Study. The Journal of the American Board of Family Practice, 18, 180-188.

9 Association of American Medical Colleges. Admission Requirements. (2010). AAMC.org [http://AAMC.org]. Retrieved February 21, 2011, from https://www.aamc.org/students/applying/requirements/ [https://www.aamc.org/students/applying/requirements/]

BY JULIANNE GAMINO

Language Barriers in Medicine

Preventing Miscommunications in Medical Settings

the researchers assessed patient and physician satisfaction and found that patients who were able to email their physician were more satisfied than patients who were limited to phone or appointment communication. Additionally, all doctors reported satisfaction with the email system.8 However, email uptake by physicians has been limited, possibly due to malpractice and workload concerns. Therefore, etablishing policies for patient-physician email correspondence may encourage its use. Since emails can be sent at work or from anywhere with a smart-phone, physicians may find that incorporating emails into their practice to be efficient. While patient interaction training takes place in medical school, undergraduate students interested in a medical career can begin preparing for these future responsibilities by developing proficient communication skills early on. For example, Penn students are required to complete the equivalent of four semesters of a foreign language. The AAMC requires that prospective medical students have completed a year of English because “the ideal physician…can communicate and write well”.9 Another domain for practicing interactions with patients and preparing for the “people” side of medicine is clinical volunteering. Interaction with individuals in a clinical setting is a good way to practice oral communication skills. Overall, strong communication skills and rapport building is something that will prove useful in a future medical career. As many Penn students prepare to enter the healthcare industry, it will be our responsibility to integrate new methods of communication with traditional methods. Yet regardless of new research, the same basic communication skills are necessary: listening closely and conveying information clearly. Both doctors and patients benefit from good communication, and with new options and strategies for improving communication, one can hope to observe lower misdiagnosis rates and improved patient outcome going forward.


References

1 Flores, G. (2006). Language barriers to healthcare in the United States. The New England Journal of Medicine, 355, 229-231.

2 Clinic Staff. (2009, June 26). Intracranial hematoma - MayoClinic.com. Mayo Clinic. Retrieved February 23, 2011, from http://www.mayoclinic.com/health/intracranial-hematoma/DS00330

3 Gany, F., Kapelusznik, L., Prakash, K., Gonzalez, J., Orta, L. Y., Tseng, C., et al. (2007). The Impact of Medical Interpretation Method on Time and Errors. J Gen Intern Med, 22(2), 319-323.

4 Regenstein, M., Trott, J., West, C., & Huang, J. (2008). In any language: improving the quality and availability of language services in hospitals. Robert Wood Johnson Foundation

5 Woloshin, S., Schwartz, L. M., Katz, S. J., & Welch, H. G. (1997). Is Language a Barrier to the Use of Preventive Services? J Gen Intern Med, 12(8), 472-477.

6 Zanchetta, M. S., & Poureslami, I. M. (2006). Health literacy within the reality of an immigrant’s culture and language. Canadian Journal of Public Health, 97(2), S26-S29.

7 Kohn, L. T., Corrigan, J., & Donaldson, M. S. (2000). To err is human: building a safer health system. Washington, D.C.: National Academy Press.

8 Williams, R. M. (1996). The Costs of Visits to Emergency Departments. New England Journal of Medicine, 334, 642-646.

9 Cohen, A. L., Rivara, F., Marcuse, E. K., McPhillips, H., & Davis, R. (2005). Are language barriers associated with serious medical events in hospitalized pediatric patients? Pediatrics, 116(3), 575-579.

10 Tandon, S. D., Parillo, K. M., & Keefer, M. (2005). Hispanic women’s perception of patient-centeredness during prenatal care: a mixed-method study. Birth, 32(4), 312-317.

benefits.6 Regular healthcare leads to better health overall; conversely, a lack of preventative healthcare can lead to an increase in emergency department visits.4 This increases costs for both patients and the institutions providing care. When patients do come to the hospital, the clinical staff may find it difficult to fully understand their patients’ medical needs. Research shows that hospitals are overwhelmed by patients’ language needs and are uncertain as to how to best address these growing demands.4 Misunderstandings due to language barriers can also cause grave medical errors, as shown in the case of the Spanish-speaking patient. Aside from causing detrimental health effects, medical errors can be very costly. In this case, the hospital was forced to pay a $71 million malpractice settlement.1 According to the Institute of Medicine’s report on medical errors, the total cost of preventable medical errors in the United States is $17 billion.8 A study of 97 patients in a particular hospital showed that hospitalized children with parents with limited English proficiency bore twice the risk of serious medical events—defined as an event that led to unintended or potentially adverse outcomes—during their stay.9 If hospitals allotted more resources toward combating language barriers, the incidence of medical errors could potentially decrease. Patients with limited English proficiency are also more likely to require costly diagnostic testing in the emergency department.9 If communication were simply more effective, providers would have a better understanding of a patient’s symptoms and condition without the need for extraneous testing. For providers, there is much that can be done to relieve this issue. It is important for providers to be sensitive to their patients and to adapt the care they give to a specific patient. A popular term for this is “patient-centered care,” defined by the Institute of Medicine as a healthcare system that is responsive to the cultural and language needs, values, and preferences of the patient.10 If providers are receptive to individual patients and their specific language and communication needs, patient communication will be more effective, resulting in better care. It is also important for providers to include the patient’s family, if possible, in care and teaching. Many cultures, including the Hispanic

culture, are very family oriented, and patients may feel more comfortable if family members are involved in their care.10 However, using family members as interpreters is not advised because miscommunications can still easily occur. As such, it is vital to employ either a clinician who speaks the patient’s native language or an interpreting service to translate whenever possible. The use of a professional medical interpreter can greatly reduce errors in communication. There are also many interpreting devices available for use in the clinical setting, such as picture boards or translator phone lines. Even with these tools, however, ensuring clear communication requires a creative and adaptable healthcare team to work effectively with patients and their families. Language barriers pose a serious issue in healthcare that can have detrimental results for patients and increase costs for healthcare providers and payers. They can also limit the effectiveness of medical care and cause provider frustration and patient embarrassment and shame. To avoid challenges in communication, it is important that clinical staff work together, use translating resources, be culturally sensitive and think creatively. With such problem solving methods available for use in the clinical setting, every patient has the right to be understood.

语言障碍

Языковой барьер

언어의 장벽barrière de la langue

språkbarrieren ? ??ASHLEY WU / GRAPHIC


Referfences

1 Case Western University, Medical Scientist Training Program (MSTP) – Clinical and Translational Scientist Training Program (CTSTP). (2006). History of MD – PhD Training at Case Western University; Perspective. Retrieved February 02, 2011, from http://mstp.cwru.edu/Program/History/history.asp.

2 Emma Alden, tape-recorded interview by Reshmi Kaur Oberoi, Philadelphia, PA, 15 November 2010.3 Andrew Rech, tape-recorded interview by Reshmi Kaur Oberoi, Philadelphia, PA, 15 November 2010.4 Dr. Peter J. Pronovost interviewed by Claudia Dreifus, “A Conversation with Dr. Peter J. Pronovost: Doctor

Leads Quest for Safer Ways to Care for Patients”, The New York Times, 08 March 2010.5 Geoffrey S. Ginsburg, MD, PhD, “Controversies in Medicine: Direct-to-consumer Genetic Testing”, Duke

Helath.org Health Articles, published18 June 2010, updated 04 August 2010,6 Columbia University MD-PhD Program. David Leung, MD/PhD, Resident in Diagnostic Radiology.

Retrieved 02 February, 2010 from, http://cumc.columbia.edu/dept/mdphd/research/leung.html.

The Physician Scientist: Setting a New Standard of Clinical CareBY RESHMI KAUR OBEROI

Individuals who participate in MD/PhD programs encompass a unique demographic because of their obligation to fulfill two roles simultaneously. As an MD/PhD matriculate, one is distinguished from one’s MD peers, as the number of applicants selected for the MD/PhD program, paid in full by the government, is usually quite low.1 Although MD/PhD matriculates often face a dilemma in choosing between their roles as clinicians and researchers, they are now exemplifying a changing role in the provision of medical care. Today’s ideal physician is not only one who diagnoses and prescribes treatments but also a scientist who contributes toward expanding the boundaries of patient care through research. MD/PhDs are poised to fulfill this new, evolving role. The first formally recognized MD/PhD program was instituted at Case Western University in 1956. True to being the first of its kind, the program’s description did not have clear expectations for its matriculates, but instead emphasized both “integration and coordination of PhD and MD training.”2 To integrate, defined as to bring together or to incorporate parts into a whole, is distinct from coordinating, defined as the harmonious adjustment or interaction of parts. One can decipher whether or not a university’s MD/PhD program leans more toward integrating the degrees or coordinating them by looking out for the following phrases used to refer to the role of the matriculates of their program: physician-researcher, a hyphenated phrase that emphasizes integration, or physician and researcher, emphasizing coordination. Clearly, the MD/PhD program is a paradox: It is both exclusive and inclusive because anyone who is qualified to become a physician has the option to pursue a post-doctoral degree in any subset of the hard sciences or social sciences. Furthermore, one can either choose to dedicate 80% of his or her time on research and 20% to clinical work, also known as the 80-20 physician-researcher paradigm, or, like one first year Penn med student pursuing a PhD in the History and Sociology of Science, choose to adhere more to the physician and researcher 50-50 paradigm—“ The sort of thing that I would love to do is find systemic problems in health policy or healthcare system and use my historical research methods to find ways to address those problems and then implement them.”2

Whether a program trains its students to blend their degrees or to conduct their roles separately in a coordinated rhythm, a first year MD/PhD student at the University of Pennsylvania commented, “There’s no difference, just some extra responsibilities. When you’re in the medical school, you’re a medical student. You don’t feel excluded like you’re part of a different culture.”3 Another MD/PhD student interviewed, who is working toward a PhD in the history of science, also considered herself a part of the overarching practitioner of medicine: “I think [medicine] is a cult… there is a lot of desire to be a part of that. There is an aura

around it that is very appealing to a lot of people. Financially, socially, not just amongst each other but amongst society—oh, I’m a doctor, I’m a medical student. It’s pretty cool and it’s well respected.” The MD/PhD program seems to be forming a new “first tier” within the medical school admissions hierarchy. Dual-degree medical practitioners tend to provide patient care that is more personalized. Patient idiosyncrasies can be collectively analyzed and further contributions can continue to be made on a broader level, applying to more people who will be affected by the same health condition. Listed as one of the one hundred most influential people in TIME magazine for the year 2008 was an MD/PhD, Dr. Peter Provonost. His motivation for earning both degrees and combining both disciplines into practice was a personal one. His father passed away at age fifty from lymphoma, but had been diagnosed with leukemia. In an interview, Dr. Provonost relayed how this experience led him to pursue a PhD in hospital safety, a social science, in addition to his medical degree: “The word ‘error’ was never spoken. But it was crystal clear. I was devastated. I was angry at the clinicians and myself. I kept thinking, ‘Medicine has to do better than this.’ A few years later… I was a physician and I’d done an additional PhD on hospital safety.”4

As is exemplified by Dr. Provonost, medicine can do better if the physician accumulates more knowledge within a discipline other than the MD’s focus on clinical, patient-interactive, medicine. This method of improving medical practice was also proven by a graduate from Boston University’s MD/PhD program. In his article, he subtly addresses how the lack of scientific mechanical knowledge by clinical physicians takes away from the welfare of their patients: “It is important for physicians to educate themselves in this exciting and uncertain new world. To do so, we need not all become experts.” The physician-scientist continues by placing the physician and the patient on the same level of intellect, emphasizing a type of humility gained from MD/PhD training.5 Another added benefit of being an MD/PhD is the constant emphasis placed on humility. Columbia University’s MD/PhD website highlights a testimony of a resident in diagnostic radiology. The testimony addresses how PhD work enables one to provide better patient care as a physician. The final point is directed toward the MD/PhD student: “Most importantly, be humble. We are not, and will never be, all-knowing.”6


FEATURES: SURGERY

Innovations in Medical Robotics: The da Vinci Surgical System

BY CARY KRAFT

Predicting the future is difficult. Fortune-tellers try to divine the fates of star-crossed lovers, stock market speculators make or lose millions by following a lead and retail manufacturers hope to discover the next big thing with every product they release. At least one prediction, however, has been easy to make: for better or for worse, the future of medicine is in robotic surgery. “Everybody asks for robotic surgery,” says Dr. Daniel Cosgrove, a urologist from Los Angeles, California, who has

The use of robotic techniques is revolutionizing surgery by allowing for faster, cleaner and safer procedures. Dr. Daniel Cosgrove, a practicing urologist, weighs in on the advantages of this rapidly developing technology.

had extensive experience using the famous da Vinci Surgical System for radical prostatectomies (removal of the entire prostate, a gland highly susceptible to cancer). “If they have to have surgery, then that is what they ask for,” says Dr. Cosgrove.1 According to a new study published in the New England Journal of Medicine, the number of robot-assisted radical prostatecomies has reached over 60,000, accounting for a substantial portion of such prostate surgeries.2 Research on robotic surgery being done at Penn has resulted in a Food and Drug Administration (FDA)-approved procedure called TransOral Robotic

This da Vinci device has an endoscopic camera as well as three movable arms that can be equipped with various functional tools. The surgeon views a three dimensional image of the operating environment and manipulates the arms of the robot from a console separate from the operating table.


Surgery for the removal of tumors in the mouth, throat and larynx.3 Though used widely in the fields of urology, orthopedics, neurology and cardiology, robotic surgical techniques will have a widespread and decisive impact on the future of medicine only if several hurdles can be overcome. Before discussing the current state of robotic surgery and its future, it is important to understand its past. In 1978, the first robotic surgical instrument, the Programmable Universal Manipulation Arm (PUMA 560), was used to hold a camera to prevent hand exhaustion and tremors during long surgeries.4 An exciting development then came with

PROBOT in the 1980s. With PROBOT, the surgeon used a generated three-dimensional model of a patient’s prostate to map out the area that needed to be resected. The robot performed a programmed sequence of motions to excise the specified area without further assistance from the surgeon.5 The Automated Endoscopic System for Optimal Positioning (AESOP) was the first surgical system that allowed the surgeon to perform solo, minimally-invasive laparoscopic surgeries in a timespan comparable to those performed by full surgical teams.4 AESOP was a camera holder that had seven degrees of freedom, which allowed it to mimic the motions of a human hand and to obtain better images of laparoscopic operations. The next innovation was ZEUS, the first surgery device that eliminated the need for the surgeon and the patient to be in the same room. With ZEUS, “a robotic arm carries an endoscope while two other manipulator arms carry interchangeable tools, such as scissors and grippers.”5 All of these arms are manipulated by a surgeon using controls situated away from the operating table.5 ZEUS is well known for being used in the first transatlantic surgery, in which a doctor in New York City operated on a patient in Strasbourg, France from over 3,800 miles away.6

The advent of the da Vinci Robot by Intuitive Surgical was a highly promising event in the history of telesurgery. This device has an endoscopic camera as well as three movable arms that can be equipped with various functional tools.7 The surgeon is presented with a three dimensional image of the operating environment and manipulates the arms of the robot from a console unconnected to the operating table. The da Vinci system—the first of its kind approved for use by the FDA—has a number of significant benefits over traditional surgery.7 According to Dr. Cosgrove, the major benefit of robotic surgery for radical prostatectomies is that it allows for “enhanced recovery for the patient; they are in and out in twenty-four hours,” whereas for traditional surgery, “recovery lasted three to five days. And patients have to wear a catheter for two to three weeks in open surgery compared to only one week for robot assisted surgery.”1

In addition to decreased recovery time, experimental data shows other benefits of robotic surgery, such as decreased blood loss when compared to classic laparoscopic surgery.8,10 Dr. Cosgrove explained that robotic surgery uses pneumoperitoneum —carbon dioxide inserted into the abdominal cavity in order to increase visibility during surgery—to create higher pressure that results in less blood loss during the procedure. This reduces the need for blood transfusions. Another benefit noted by Dr. Cosgrove is post-recovery aesthetics. In a traditional open radical prostatectomy, the patient is left with a scar from the belly button to the pelvic bone, since the surgeon must cut a large incision in order to have enough space to operate. With the da Vinci Robot, Dr. Cosgrove says his patients are left with only five one-centimeter-long scars where the laparoscopic tools were inserted.

This PUMA Robotic Sensor Arm is a more updated version of the Programmable Universal Manipulation

Arm (PUMA 560) created in 1978. It, along with the PUMA 560, were precursors to the Da Vinci Robot.

This particular model was created at the NASA Ames Research Center for use in telepresence surgery, which

integrates medicine and virtual reality. Source: biomed.brown.edu


Despite the various benefits of robotic surgery, there are still obstacles to overcome. For instance, the da Vinci robotic system costs nearly 1.75 million dollars, which does not even include the one hundred thousand-dollar yearly licensing agreement.11 This exorbitant cost prevents many hospitals from being able to afford the system, which raises ethical questions about equitable access to care. One study found that over 75% of surgeons polled would not be able to incorporate a system costing more than five hundred thousand dollars into their practices.12 This indicates that only the wealthiest of practices—and therefore the most affluent clientele—would have access to the surgical system. Despite this, the newest da Vinci system released in 2009 came with an increased price tag along with updated capabilities. According to the Intuitive Surgical website, by June of 2010, “there [had been] 1,571 systems installed worldwide,” which included “1,160 in the United States” alone, yet the company has no published intent to reduce the price of their patented system; cost will thus continue to be an influential factor in robotic surgery for the foreseeable future.7

Furthermore, there is a steep learning curve for using the device. A surgeon’s initial surgeries using the da Vinci Robot can take twice as long as conventional surgery and play host to a number of complications. For radical prostatectomies, these complications include longer hospital stays, increased duration of catheterization, incontinency, impotency and cancer recurrence in the long term. Dr. Cosgrove acknowledges that, hypothetically, “nobody wants to be my first patient on the robot,” especially in a city like Los Angeles, where “there are a lot of people who are very skilled in surgery and I can’t tell a person that I would do the best job.”1 The training program is extensive and exhaustive, and requires a trip to the Sunnyvale headquarters of Intuitive Surgical for lectures and lab time spent practicing techniques on pigs. A proctor from the company must then observe the surgeon until he or she becomes competent enough to perform the surgeries on their own.1 The high cost of the da Vinci Robotic System and the steep learning curve are significant barriers to the system’s widespread use. A high purchasing cost and an extended education period provide distinct initial challenges to purchasing a new da Vinci Robot. Any hospital that wishes to obtain such a system must carefully weigh the benefits that come with using robotic surgery against the inherent costs in the initial investment. Regardless of the hurdles that must be overcome, there are high hopes for robot-assisted surgery in the future. Speaking about his own field, Dr. Cosgrove conjectured, “I certainly think this is the future of urologic surgery. And it may soon come down to all radical prostatectomies being done this way.”1 Dr. Cosgrove has high hopes that the obstacles to widespread application will be overcome. This system will lead to more precise surgeries with better aesthetic results and quicker recovery times as the practice eventually becomes more fully accepted in the medical community.

References

1 Cosgrove, Dr. Daniel. (February 9, 2011) Phone Interview2 Barbash, G., & Glied, S. (2010). New Technology and Health Care Costs– The Case of

Robot-Assisted Surgery. New England Journal of Medicine, 363(8), 701-704.3 FDA Clears TransOral Robotic Surgery – Developed at Penn – for Tumors of Mouth,

Throat and Voice Box. (n.d.). Penn: University of Pennsylvania: Research at Penn: Health. Retrieved February 10, 2011, from http://www.upenn.edu/researchatpenn/article.php?1703&hlt

4 Kalan, S., Chauhan, S., Coelho, R., Orvieto, M., Camacho, I., Palmer, K., et al. (2010). History of Robotic Surgery. Journal of Robotic Surgery, 4, 141-147.

5 Davies, B. (2000). A Review of Robotics In Surgery. Proceedings of the Institution of Mechanical Engineers, 214, 129-140.

6 Minkel, J. (2001, September 20). First Complete Trans-Atlantic Robotic Surgery. Scientific American. Retrieved February 9, 2011, from www.scientificamerican.com/article.cfm?id=first-complete-trans-atla

7 Intuitive Surgical - da Vinci Surgical System. (n.d.). Intuitive Surgical, Inc. - da Vinci Surgical System. Retrieved February 10, 2011, from http://intuitivesurgical.com/products/davinci_surgical_system/

8 Menon, M., Tewari, A., Peabody, J., Shrivastava, A., Kaul, S., Bhandari, A., et al. (2004). Vattikuti Institute prostatectomy, a technique of robotic radical prostatectomy for management of localized carcinoma of the prostate: experience of over 100 cases. Urology Clinics of North America, 31, 701-717.

9 Wood, D., Schulte, R., Dunn, R., Hollenbeck, B., Saur, R., Jr., J. W., et al. (2007). Short-Term Health Outcome Differences Between Robotic and Conventional Radical Prostatectomy. Urology, 70(5), 945-949.

10 Kumar, R., & Hemal, A. (2005). Emerging role of robotics in urology. Journal of Minimal Access Surgery, 1(4), 202-210.

11 Grover, S., Tan, G., Srivastava, A., Leung, R., & Tewari, A. (2010). Residency Training Program Paradigms for Teaching Robotic Surgical Skills to Urology Residents. Current Urology Reports, 11, 87-92.

12 Hanly, E., & Talamini, M. (2004). Robotic abdominal surgery. The American Journal of Surgery, 188, 19-26.

With advances in telemedicine (remote medical consulting or surgical procedures), transcontinental, or at the very least, international, surgeries have become a realistic possibility. This leads to interesting ethical quandaries, as legal battles regarding malpractice and negligence take on new jurisdictional aspects. For instance, if a patient is operated on in the United States by a surgeon in Germany, under what laws would a dispute be settled? Traditional sources state that a case is “actionable where its effects are felt,” so, in the aforementioned case, the patient’s local court in the United States would have jurisdiction, provided the patient wanted to try the case there.1 However, other appropriate insurance and financial matters must be considered in that a doctor may only be covered by malpractice insurance in a specific country. In certain instances, this can warrant trying the case in the physician’s country so that the patient can obtain proper recompense. From an ethical perspective, electronic eavesdropping is a concern in telemedicine, and maintaining confidentiality through both appropriate electronic firewalls and discreet medical technicians on both ends is key. Ethical and legal quandaries must be clarified and solved “so that jurisdictional differences will not obstruct patients’ access to telemedical and robotic surgical services.”2

1 Briggs, A. (2008). The conflict of laws. (2nd ed.). Oxford : Oxford University Press.2 Dickens, B., & Cook, R. (2006). Legal and ethical issues in telemedicine and robotics. International Journal of

Gynecology and Obstetrics, 94, 73-78.

Ethics and Legality in International Medicine


Immunity and Organ Transplantation: Searching for a Solution

BY AVANTHI RAGHAVAN The patient, Richard Herrick, was admitted to the Peter Bent Brigham hospital in Boston on October 26, 1954 with chronic glomerulonephritis, an inflammatory renal disease that impairs the kidney’s filtration ability. As it became evident that Richard faced imminent death, his identical twin Ronald offered to donate one of his kidneys to his brother. At 11:15 A.M. on December 23, 1954, a team of transplant surgeons under the supervision of Dr. Joseph E. Murray anastomosed, or connected, the renal artery and vein from the donated kidney to Richard’s own blood vessels, and breathlessly awaited the result. “The entire kidney became turgid and pink immediately,” Murray later reported, and “clear urine [began] flowing copiously.”2 Richard survived for another eight years. For his remarkable achievement, Murray was awarded the 1990 Nobel Prize in Medicine.1,3 Organ transplantation has revolutionized the treatment of individuals with end-stage organ failure. Yet more than five decades later, doctors still grapple with a major hurdle when it comes to successful transplantation: immune rejection. The key to Murray’s operation lay in the fact that

Eight surgeons, gowned and masked, cluster around the operating table of

their anesthetized patient under the glare of overhead lamps. Several physicians,

garbed in white lab coats, closely monitor the proceedings from the open doorway. This scene, memorialized in Joel Babb’s oil painting The First Successful Kidney

Transplant, is anything but ordinary.1

LINDA YIN / PHOTO


the organ donor and recipient were genetically identical—Richard’s immune system could not recognize Ronald’s kidney as a foreign entity and mount an immunologic attack. Practically speaking, such isografts between identical individuals are a clinical rarity; the majority of transplant cases are instead allografts between genetically dissimilar individuals.4 On the molecular level, graft rejection is caused by incompatibility between the donor and recipient’s HLA (human leukocyte antigen) genotype. In humans, the HLA locus encodes a family of highly variable proteins that are expressed at the surface of nearly all cells of the body. The HLA antigens play a critical role in fostering the immune system’s awareness of “self ” versus “nonself.” Cells exhibiting “nonself ” HLA are recognized by host T cells (mediators of cellular immunity), which infiltrate the grafted organ and cause either cellular lysis or necrosis (death) of the foreign tissue. Clinical manifestations of this “host-versus-graft” disease include fever, pain at the transplant location, and loss-of-function in the transplanted organ. Because the HLA locus is incredibly polymorphic, the chance that two individuals will be precisely matched at this locus is slim to none—except, of course, in the fortuitous case of identical twins.5 While strategies such as HLA typing can identify reasonable compatibility between donor and recipient, thus somewhat reducing rejection risk, immunosuppressive therapies are the primary line-of-defense against host-versus-graft disease. The first breakthrough in immunosuppression was achieved in the 1960s using a combination of azathioprine and corticosteroids—molecules that indiscriminately prevent immune cell proliferation and cytokine production (cytokines are signaling proteins secreted by immune cells). Unfortunately, the immunosuppressive effect of the combination therapy proved too powerful; patients suffered high morbidity due to heightened susceptibility to various unrelated infections.4 The development of cyclosporine a few decades later addressed this problem by specifically targeting T cell response ability, a strategy that reduced mortality as well as dramatically improved one-year graft survival rates. Currently, therapies involving co-administration of these original immunosuppressants with newly developed varieties have increased short-term allograft survival prospects to 80-90%.6

Unfortunately, immunosuppressive agents have failed to enhance long-term (5-10 years) graft survival. In such cases of chronic allograft dysfunction, immunologic factors are not the sole basis for organ rejection—the donor’s age, organ quality, and transplantation-induced tissue injuries are also determinants of graft longevity.4,7 In addition to the obvious danger of lifelong immunosuppression, prolonged use of many of these agents has been shown to have an oncogenic effect.8

The insurmountable problem of host-versus-graft disease and the shortcomings of traditional immunosuppressive therapy have led researchers to seek alternative methods of organ transplantation. In the December 2008 issue of The Lancet, Macchiarini et al reported an unprecedented advance in transplant history:

the engineering of a human trachea from adult stem cells. The patient, Claudia Castillo, was a 30-year-old mother who had suffered left lung and partial airway collapse due to severe tuberculosis. In a landmark procedure, researchers removed the trachea of a cadaveric donor and denuded it of living cells, exposing an underlying connective tissue scaffold. Meanwhile, Castillo’s own bone marrow stem cells were extracted and cultured in vitro under conditions conducive to chondrocyte, or cartilage cell, differentiation. Doctors then seeded chondrocytes onto the donor trachea and allowed them to grow for several days, at which point the engineered trachea was used to replace Castillo’s existing airway. Critically, no immune rejection was observed, and Castillo was discharged from the hospital ten days later.9 Castillo’s success story offers immense promise for the field of organ transplantation. However, engineering individualized grafts for transplant patients is not the only possible option looming on the horizon. For example, partial bone marrow irradiation of the transplant recipient may be another alternative to immunosuppression; the radiation destroys host T cells that mediate immune rejection. Prior to the transplant procedure, the patient received an infusion of bone marrow from the same individual who had donated the organ; the donor T cells, which recognized the transplanted organ as “self,” do not mount an immunologic attack. (10) As demand for donated organs burgeons, so does the pace of transplant technology. Scientists continue to devise increasingly creative ways of circumventing the once impossible hurdle of immune rejection. Successful transplant cases, such as that of Richard Herrick, are no longer the exception, but are now the norm. For thousands of patients worldwide whose lives hinge on much-needed organ transplantations, the future looks bright.

References

1 Schatzki, S. (2003, July 1). Medicine in American art: The first kidney transplantation. American Journal of Roentgenology, 181(1), 190.

2 Merrill, J. P., Murray, J. E., Harrison, J. H., & Guild, W. R. (1956, January 28). Successful homotransplantation of the human kidney between identical twins. The Journal of the American Medical Association, 160(4), 277-282.

3 Morris, P. J. (2004, December 23). Transplantation—A medical miracle of the 20th century. The New England Journal of Medicine, 351(26), 2678-2680.

4 Sayegh, M. H., & Carpenter, C. B. (2004, December 23). Transplantation 50 years later—progress, challenges, and promises. The New England Journal of Medicine, 351(26), 2761-6.

5 Murphy, K. M., Travers, P., & Walport, M. (2007). Janeway’s Immunobiology (7th ed.). Garland Science.

6 Kahan, B. D. (1989, December 21). Cyclosporine. The New England Journal of Medicine, 321, 1725-1738.

7 Pascual, M., Theruvath, T., Kawai, T., Tolkoff-Rubin, N., & Cosimi, A. B. (2002, February 21). Strategies to improve long-term outcomes after renal transplantation. The New England Journal of Medicine, 346, 580-590.

8 Gutierrez-Dalmau, A., & Campistol, J. M. (2007). Immunosuppressive therapy and malignancy in organ transplant recipients: A systematic review. Drugs, 67(8), 1167-1198.

9 Macchiarini, P., Jungebluth, P., Go, T., Asnaghi, M. A., Rees, L. E., Cogan, T. A., Martorell, J. et al (2008, December 13). Clinical transplantation of a tissue- engineered airway. The Lancet, 372(9655), 2023-2030.

10 Kawai, T. et al (2008 January 24). HLA-mismatched Renal Transplantation without Maintenance of Immunosuppression. The New England Journal of Medicine, 358, 353-361.

Scientists continue to devise increasingly creative ways of circumventing the once impossible hurdle of immune rejection.

LINDA YIN / PHOTO


Severe Traumatic Brain Injuries and Decompressive Craniectomy:

Current Debates over Treatment Options

Dr. Jam Ghajar, president of the Brain Trauma Foundation, states that the treatment given to the Congresswoman would not have been possible just fifteen years ago.2 Yet according to Dr. Sherman Stein, Clinical Professor of Neurosurgery at the Hospital of the University of Pennsylvania (HUP), this statement is not entirely true. Dr. Stein explains that the surgery was actually conceptualized in the 1960s but was quickly abandoned due to strong objections over its validity, after which it was buried for decades until re-emerging roughly fifteen years ago.3 In effect, Giffords’ story of tragedy and hope has helped unveil an age-old debate in neurosurgery: the difficulties and hesitations towards finding better treatment plans for STBIs. Traumatic brain injuries (TBIs) occur when the brain experiences a blunt external force. In descending order, the leading causes of TBI are: vehicular accidents, collisions with other objects and violent assaults like the one in Tucson. (4) TBIs are also classified as either closed or penetrating. Closed injuries show no open wounds, but can be more life threatening than penetrating injuries. (5) The injuries also receive a rating based on the fifteen-point Glasgow Coma Scale (GCS), a measurement used to assess the patient’s level of consciousness. Injuries with a GCS score lower than eight are considered STBIs and are the most difficult to treat.6

One common and dangerous complication among STBI patients is a rapid increase in intracranial pressure (ICP).7 This rise in pressure can slow much-needed blood flow to the brain and cause herniation, which is a shifting of the structures within the brain.8 Efforts to advance the treatment of STBIs have generally centered

on the early detection and mediation of increased ICP. One innovation is the still-controversial surgery referred to as a decompressive hemi-craniectomy, in which part of the skull five to six inches in diameter is excised from one side of the brain in order to alleviate the extra pressure within.9 This seemingly radical surgery has proven to have immense positive effects on the patients involved, especially for military personnel injured in combat.10 Severe blast injuries from improvised explosive devices bring soldiers to the closest care center, where often removing a part of their skull is the only way to manage increased ICP. For some, like Sergeant David Emme, decompressive craniectomy can save lives and restore most cognitive functions after only five months of recovery.11 Dr. Stein is also very optimistic of the procedure: “My experience shows that the outcomes at six months after hemi-craniectomy are quite good, since a large percentage of those patients were expected to not survive at all.”3

Indeed, a recent study from France shows that in forty patients with intractably high ICP levels, decompressive cranietomies allowed twenty-five percent of them to recover to the point of social rehabilitation. In other words, the surgery helped those at high risk of brain death to recover to a manageable state. This study also shows that the procedure is more successful when used as a last resort.12 Current clinical practice seems to adhere to these results. Dr. Stein reveals that HUP usually tries many other treatment options on patients before even considering decompressive craniectomy. Dr. Stein explains that treatment for STBI patients begins with nursing steps, such as ensuring proper breathing patterns, which helps maintain high oxygen

BY LINDA YIN

On January 8, 2011, shots rang through a shopping center in Tucson, Arizona and shook an entire nation. Six of the victims died, but one, Arizona Congresswoman Gabrielle Giffords, miraculously survived a gunshot wound to the head. The target, Rep. Giffords, suffered a severe traumatic brain injury (STBI) but gained a second chance at life through what the media advertises as a new and radical surgical procedure called a decompressive craniectomy.1


and low carbon dioxide levels to prevent swelling in the brain. Doctors must also keep a close eye on the patients’ blood pressure, making sure that it is in a normal range and that the patient is not being loaded with fluids. “Then we start looking at things that can improve ICP, such as hypertonic salt solution or mannitol, which is a sugar that doesn’t get through the blood brain barrier, so it sort of dries out the brain by drawing water out of the brain. There’s also hyperventilation, in which we increase the breathing to lower carbon dioxide levels,” Dr. Stein describes.3 In some patients, however, intracranial hypertension is uncontrollable by traditional methods, and alternative treatments must be considered to prevent excessive manipulations upon the brain. For example, prolonged hyperventilation can also restrict blood flow to the brain and cause a stroke.13 In these cases, doctors have two options: either put the patient in a medically induced coma to lower brain metabolism or perform a decompressive craniectomy. The former has proven successful in a large amount of cases, though doctors are unsure of the specific mechanisms by which it operates.14 However, the procedure is not without risks, for the coma brings patients’ heart rates to dangerously low levels. As a result, many neurosurgeons would rather opt for the hemi-craniectomy. In fact, HUP recently participated in a DECRA (decompressive craniectomy) trials study assessing the effectiveness of resorting to hemi-craniectomies over medically induced comas in cases of uncontrollable intracranial hypertension. The DECRA trials, along with the RESCUEicp (Randomised Evaluation of Surgery with Craniectomy for Uncontrollable Elevation of Intra-Cranial Pressure) study, are the only two major ongoing international studies assessing the effectiveness of decompressive craniectomies.15 Those against the decompressive craniectomy feel that it often does more harm than good. One recent study in Australian hospitals conducted between 2004 and 2009 showed that many complications arise from the initial surgery. Problems include, but are not limited to, herniation of the cortex through the hole in the skull, seizures and infections.16 Yet others argue that these complications may arise regardless of a decompressive craniectomy, and are often common to all STBI patients. In fact, even after successful surgeries with months of physical rehabilitation, many patients still often walk away with lifelong physical, cognitive, behavioral and emotional consequences, none of which can easily be repaired.4 As for future decisions over the surgery’s validity, Dr. Stein looks forward to RESCUEicp’s findings for guidance. Although RESCUEicp is expected to analyze its data in the coming months, the DECRA trials may soon suspend investigations due to lack of viable data. Dr. Stein attributes the stagnant and difficult nature of STBI research to the complex variations among

References

1 Murray, S., & Horwitz, S. (2011, January 9). Congresswoman shot in tucson rampage . The Washington Post, p. A01.

2 Healy, M. (2011, January 24). Treatment Advances improve survival rates. Los Angeles Times. p.E4

3 Stein, Sherman. Interview4 Langlois, JA., Rutland-Brown, W., & Wald, MM. (2006). The epidemiology and

impact of traumatic brain injury: a brief overview. Journal of Head Trauma Rehabilitation, 21(5), 375–378.

5 Maas, AI., Stocchetti, N., & Bullock, R. (2008). Moderate and severe traumatic brain injury in adults. Lancet Neurology, 7(8), 728–41.

6 Saatman, KE., et al. (2008). Classification of traumatic brain injury for targeted therapies. Journal of Neurotrauma, 25(7), 719–738.

7 Parikh, S., Koch, M., & Narayan, RK. (2007). Traumatic brain injury. International Anesthesiology Clinics 45(3), 119–35.

8 Moppett, IK. (2007). Traumatic brain injury: Assessment, resuscitation and early management. British Journal of Anaesthesiology 99(1), 18–31.

9 Sternberg, S. (2011, January 13). Radical surgery for brain injury can ease skull pressure. USA Today, p. A.5.

10 DuBose, JJ., et al. (2011). Isolated severe traumatic brain injuries sustained during combat operations: demographics, mortality outcomes, and lessons to be learned from contrasts to civilian counterparts. Journal of Trauma 70(1), 11-18.

11 Okie, S. (2005). Traumatic brain injury in the war zone. New England Journal of Medicine, 352(20), 2043-2047.

12 Albanèse, J, et al. (2003). Decompressive craniectomy for severe traumatic brain injury: evaluation of the effects at one year. Critical Care Medicine, 31(10), 2535-2538.

13 Curry, Rebecca, et al. (2008). Incidence of hypo- and hypercarbia in severe traumatic brain injury before and after 2003 pediatric guidelines. Pediatric Critical Care Medicine, 9(2), 141–146.

14 Marshall, GT., et al. (2010). Pentobarbital coma for refractory intra-cranial hypertension after severe traumatic brain injury: mortality predictions and one-year outcomes in 55 patients. Journal of Trauma, 69(2), 275-83.

15 Li, LM., et al. (2010) Review article: the surgical approach to the management of increased intracranial pressure after traumatic brain injury. Anesthesia Analog, 111(3), 736-48.

16 Honeybul, S., & Ho, KM. (2010). Long term complications of decompressive craniectomy for head injury. Journal of Neurotrauma. Advance online publication. doi:10.1089/neu.2010.1612.

17 León-Carrión J, Domínguez-Morales Mdel R, Barroso y Martín JM, Murillo-Cabezas F (2005). “Epidemiology of traumatic brain injury and subarachnoid hemorrhage”. Pituitary 8 (3-4): 197–202.

“My experience shows that the outcomes at six months after hemi-craniectomy are quite good, since a large percentage of those patients were expected to not survive at all.”

injuries and the high natural mortality rates: “We feel that there is a certain group of people who are [what the Army refers to as] FUBAR (F***** Up Beyond All Recognition), and there’s nothing that can salvage that. Most of us suspect that it’s roughly 15% of people who are in comas after severe closed head injury, and a much higher percentage for gunshot wounds. We know our present level of treatment is imperfect, but we don’t know how far we are from that [15%] group.”3 Most of the current research aims to bridge this gap between the observed and absolute mortality rate. Since new treatments are difficult to develop and test, current studies are usually centered on a meticulous refinement of the existing surgical and non-surgical options. These doctors understand that a cure for STBIs may never be achievable, but each additional life saved justifies the ongoing debates and continued research in optimizing treatment outcomes.

CAUSES OF TRAUMATIC BRAIN INJURIES IN THE U.S.17

39% Firearms

34% Vehicle Accidents

17% Other

10% Falls


Restoring Voice: The Promise of Laryngeal Transplantation

Eleven years ago, Brenda Jensen sustained irreparable damage to both her larynx and her trachea. Jensen, 52, had pulled on her ventilation tube while sedated and was told that she would have to speak through an electronic voice box for the rest of her life (1). Continuously using the “electrolarynx” for speech was a demanding endeavor that ultimately produced an unfamiliar, robotic voice. Furthermore, she was forced to breathe through a tracheostomy tube that ran through a hole in her trachea. As a result, she also lacked an olfactory sense.2 The “electrolarynx” brought with it several major social inconveniences as well. The physical frustration notwithstanding, Jensen resented all the awkward stares whenever she spoke and felt ashamed that her own grandchildren had never heard her voice.1,3 All things

considered, the lack of a voice took a heavy toll on her life, and she became determined to break the onerous cycle. In January 2011, a pioneering surgical team at UC Davis Medical Center rose to the occasion and performed a most spectacular surgery: a laryngeal transplantation, or a transplant of the larynx. Jensen became the second person in history to have successfully undergone this complex procedure. The first was a man named Timothy Heidler, who underwent successful laryngeal transplantation in 1998. However, his thyroid and trachea, unlike Jensen’s, were functional and remained intact. Jensen thus required a more comprehensive procedure.5 The larynx is said to be “one of the most sophisticated neuromuscular organs in the body”.4 Having it transplanted along with the trachea and thyroid is a remarkable feat of innovation, involving several complex microsurgical techniques and immense teamwork.

THE PROCEDUREDuring Jensen’s 18-hour long procedure, the surgeons removed the larynx, the thyroid gland and a large portion of the trachea from an anonymous donor. They then proceeded to replace Jensen’s damaged counterparts with these functional organs.1 The procedural intricacies of Jensen’s transplantation are revealed in the detailed reports of Timothy Heidler’s procedure. To first prepare for the surgery, the doctors gave Heidler immunosuppresants so that his immune system would not attack the foreign cells of the donor larynx.6 They then removed the donor larynx and tested it in a saline solution to ensure that it would permit adequate blood flow and was otherwise healthy.1 After the doctors had removed Heidler’s damaged larynx, the next task was to attach his blood vessels to

those of the donor. As the attachment began, they anastomosed, or surgically attached, the donor’s right internal jugular vein to Heidler’s large common facial vein and the donor’s right superior thyroid artery to Heidler’s (see figure). To correctly position the new larynx, the doctors removed a portion of Heidler’s trachea, split and repositioned his thyroid, but left his hyoid bone intact for later sutures. They then made three permanent sutures, each a centimeter apart, between Heidler’s hyoid bone and the donor thyroid cartilage. The larynx was finally elevated and fixed to the hyoid bone.6 The remaining tasks involved attaching the trachea and some final blood vessels. The doctors proceeded to suture the donor’s tracheal wall to Heidler’s. To finish, they anastomosed the donor’s left middle thyroid vein to Heidler’s left internal jugular vein and attached the two corresponding superior laryngeal as well as right recurrent laryngeal nerves.6 As a result of the surgery, both Heidler and Jensen have been able to speak without any external aid; in fact, they both speak in their own voices. This is because voice is a function of how sound resonates through the mouth and nose and is then formed by movement of the tongue and lips. Jensen has been adapting well to her new larynx and doctors say that her feeding tube might be removed soon, providing a full recovery after the decade-long ordeal.2

WHY THE THIRTEEN-YEAR GAP?A surprising thirteen-year long gap separates the first and the second laryngeal transplants. An important reason for this is that organ transplants are customarily performed because they are life-saving procedures. However, while the laryngeal transplant is certainly a life-changing procedure, it is by no

BY DEVAN MEHTA AND VIHANG NAKHATE

WIKIMEDIA COMMONS / GRAPHIC


References

1 “Larynx Transplant On Calif. Woman Successful : NPR.” NPR : National Public Radio : News & Analysis, World, US, Music & Arts : NPR. N.p., 20 Jan. 2011. Web. 7 Feb. 2011. <http://www.npr.org/2011/01/20/133082678/larynx-transplant-on-california-woman-successful>.

2 Larynx transplant: Q&A. (n.d.). UC Davis Health System. Retrieved January 31, 2011, from www.ucdmc.ucdavis.edu/welcome/features/2010-2011/01/20110126_larynx_transplant_qa.html

3 Voice Box Transplant Lets Woman Speak Again. (2011, January 20). CBS News. Retrieved January 31, 2011, from www.cbsnews.com/stories/2011/01/20/national/main7266250.shtml

4 Gallgher, J. (2011, January 20). Brenda Jensen’s voice restored after larynx transplant. BBC News Health. Retrieved January 31, 2011, from www.bbc.co.uk/news/health-12228027

5 BBC News | HEALTH | Voicebox transplant man can sing. (n.d.). BBC News - Home. Retrieved February 6, 2011, from http://news.bbc.co.uk/2/hi/health/1361534.stm

6 et al., M. S. (2011, May 31). Laryngeal Transplantation and 40-Month Follow-up. The New England Journal of Medicine . Retrieved February 6, 2011, from http://www.nejm.org/doi/full/10.1056/NEJM200105313442204?hits=10&andorexactfulltext=and&FIRSTINDEX=430&FIRSTINDEX=430&SEARCHID=1&searchid=1&COLLECTION_NUM=51&resourcetype=HWCIT&resourcetype=HWCIT&andorexacttitleabs=and&

7 Laryngectomy Basics. (n.d.). The International Association of Laryngectomee’s. Retrieved February 6, 2011, from http://www.larynxlink.com/Library/faqs/FAQ16.htm

8 Coghlan, A. (2011, January 21). Woman speaks after pioneering voice box transplant. NewScientist. Retrieved January 31, 2011, from www.newscientist.com/article/dn20013-woman-speaks-after-pioneering-voice-box-transplant.html

9. Nogueira, J., Hermann, D., Americo, R., Filho, I. B., Stamm, A., & Pignatari, S. (2007). A brief history of otorhinolaryngolgy: otology, laryngology and rhinology .Revista Brasileira De Otorrinolaringologia, 73(5), 693-703.

means lifesaving. After undergoing an organ transplant, a patient must continue to take immunosuppressant drugs, which can cause infections, lead to certain cancers and decrease life expectancy. Ideally, the potential benefit of a life-saving operation will significantly outweigh the risk of immunosuppressant side effects.1 As a diabetic who had undergone transplantations of her kidney and pancreas in 1998, Jensen had already been taking immunosuppressants and therefore did not need to enhance her drug cocktail after the transplant.1 Another key component is simply that the procedure is new, and researchers are continually learning about potential refinements.

CURRENT MEDICAL ALTERNATIVESFor those who are not willing to risk the immunosuppressant side effects, other ways to deal with a damaged larynx and trachea are available. When considering alternatives, one must account for both proper breathing and speech. With regards to breathing, the tracheotomy is a commonly chosen procedure that involves making an incision through the neck to create a direct airway to the trachea. A tracheostomy tube is then inserted into the stoma, or hole created in the neck, to allow for breathing.7

Numerous alternatives for oral communication after laryngeal damage are also available. A common option is the electrolarynx, a hand held electromechanical device that can be positioned against the site of laryngectomy. It produces vibrations, as would a vocal cord, to mimic normal speech. Unfortunately, the resulting sound is rather coarse and metallic. An alternative to the electrolarynx is a Tracheoesophageal Puncture. In this process, a puncture is made between the tissue of the trachea and the esophagus. A shunt valve is then placed in the puncture to ensure that the hole does not close. As a result, the patient can close the stoma and force air through the esophagus and vocal folds to produce speech. In addition, there exists a technique known as esophageal speech, whereby a patient can suck in air and force speech through belches. Though this is a rather crude method, it can be effective if mastered.7 A final option, of course, is to avoid speech altogether and to cultivate a different

mode of communication such as sign language. But overall, none of these options fully restore a patient’s normal lifestyle.

THE ROAD AHEADBased on Jensen’s landmark operation, researchers hope to develop more sophisticated and refined means of approaching laryngeal disorders. The use of stem cells, for instance, has garnered much attention.2 If a larynx could be regenerated for a specific patient using stem cells, the need for immunosuppressants—the most detrimental requisite of the transplant—would be circumvented, allowing for those transplants that are not necessarily life-saving to become more commonplace. Alternatively, Martin Birchall of University College London proposes a distinct use of stem cells. He claims that if the donor organ is chemically stripped of all donor specific cells and then coated with the patient’s own stem cells, it is possible for transplantation to occur without rejection.8 Birchall also says that the knowledge gained from this surgery can even “open the door to better facial transplants”.4 Meanwhile, Dr. Anthony Monaco at Harvard Medical School believes that additional research on safer immunosuppressant drugs promises easier access to laryngeal transplantations in the near future.5 The potential for breakthroughs in laryngeal transplantations is clearly a powerful driving force for further research. Yet, there exists another force, one that fundamentally drives both surgical and medical science—the goal to enhance the human experience. Indeed, the surgeons at UC Davis

said that “one of the biggest benefits of this transplant can be seen in Ms. Jensen’s smile”.1 The surgery gave Brenda Jensen’s life a new direction and definition. It endowed her with a most special gift—a gift of voice, of unrestricted speech. The remarkable success of the second laryngeal transplant in history has indeed been momentous. It has provided a stepping-stone for translating breakthroughs in current research into realizable treatments of the future.

The varied history of laryngology dates back to as far as 3600 B.C.E. in Egypt, where tomb drawings depict what appear to be laryngeal surgeries. Indian, Roman and Greek scholars also documented the larynx’s anatomy and function; Leonardo da Vinci and Michelangelo would later precisely diagram laryngeal structure based on human dissections. Laryngology would not see significant progress, however, until the 19th century, which saw rapid advancements in surgical and examination techniques. The 20th century also saw developments in fiber optics and radiation therapy, as well as collaboration with other specialties, which paved the way for more effective treatments. Today, the laryngeal transplant procedure that changed Jensen and Heidler’s lives appears to be the next step in this remarkable field.9

Origins of Modern Laryngology


Every year, seasonal allergies account for approximately 8 million outpatient office visits. This is mainly due to the increase in pollen and airborne allergen levels in the spring season.1 Although our immune systems protect us from airborne pathogens, at times they can react to compounds that are not particularly dangerous. There is evidence that our diets contribute to how we react to these allergens. A study in the American Journal of Clinical Nutrition suggests that our immune systems are so reactive because of the abundance of pro-inflammatory foods and the scarcity of anti-inflammatory foods in the modern diet.2 Therefore, it would appear that dietary changes might decrease the incidence of common allergies. Environmental allergens usually enter through the nose and bind to the moist mucosal surface of the upper nostril and sinus area. Immune cells called macrophages then engulf allergens and present pieces of them to B cells. The body produces many different types of B cells, one of which will be activated when its receptor binds to the fragment of the allergen, also known as an antigen. The now-activated B cells differentiate into plasma cells, which release proteins called antibodies. These particular antibodies,

An Alternative Approach to the Treatment of Allergies

called IgE antibodies, have two receptors– one binds to the same type of antigen that the original B cell was bound to, and another that, binds to a mast cell. Mast cells hold vesicles containing histamine and other compounds that lead to the common symptoms of allergies.3

Activated mast cells release their vesicles into the extracellular space causing an inflammation cascade. There are two important groups of molecules that are held within compound storing granules inside the mast cells. The first group, the preformed mediators, contains histamine and enzymes that speed up the inflammatory process. These compounds lead to the familiar symptoms of rhinitis (nasal congestion and irritation). These events happen within minutes, and are collectively referred to as the inflammatory response.2

The other group of molecules is made after mast cell activation and is composed of cytokines, chemokines, and lipid mediators. The cytokines are primarily involved in maintaining the activity of histamine, as well as in promoting the activation and production of eosinophils, powerful white blood cells that help kill pathogens. In the inflammation cascade, histamine normally binds to receptors on blood vessels and unmyelinated nerve fibers which increases the permeability of blood

vessels and causes the itching associated with allergies. Furthermore, chemokines attract more white blood cells to the area, while lipid mediators help prolong the inflammatory response. This phase, called the late phase reaction, begins eight to twelve hours after initial antigen recognition and lasts until antigen exposure ceases.2

However, some natural and synthetic substances can interfere with this cascade at several points. Currently, the most popular drugs on the market are second-generation antihistamines, such as Zyrtec and Claritin. As the name implies, these drugs counter the function of histamine by blocking the target receptors to which histamine would normally bind. Furthermore, there is evidence that the second-generation antihistamines possess some anti-inflammatory effects besides histamine receptor blocking.4 Anti-inflammatory responses are beneficial because they directly counter the inflammatory symptoms of allergies. The anti-inflammatory effects of current medications block many different points on the inflammation pathway. For example, there is evidence that Zyrtec impedes the activity of eosinophils and makes biological surfaces less adhesive to white blood cells.5 Some other antihistamines reduce cytokine expression.4 All of this would lead to

BY NISSAR AHMED

RESEARCH

Immune pathway of activated B-cells and macrophages in response to allergens

DIANA LU / GRAPHIC


References

1 J. Bousquet, Allergic Rhinitis and its impact on Asthma (ARIA). Clinical & Experimental Allergy Reviews, 3, 43–45 (2003). 2 E. Mantzioris, L. G. Cleland, R. A. Gibson, M. A. Neumann, M. Demasi, M. J. James. Biochemical effects of a diet containing foods

enriched with n-3 fatty acids. The American Journal of Clinical Nutrition, 72, 42-48 (2000). 3 K. M. Murphy, P. Travers, M. Walport. Janeway’s Immunobiology. (Garland Science, ed. 7, 2007). 4 S. Hayashi, S. Hashimoto, Anti-inflammatory actions of new antihistamines. Clinical & Experimental Allergy. 29, 1593–1596

(1999). 5 R. M. Naclerio, D. Proud, A. Kagey-Sobotka, L. Freidhoff, P. S. Norman, L. M. Lichtenstein, The effect of cetirizine on early allergic

response. The Laryngoscope. 99, 596–599 (1989). 6 D. Kempuraj, B. Madhappan, S. Christodoulou, W. Boucher, J. Cao, N. Papadopoulou, et al. Flavonols inhibit proinflammatory

mediator release, intracellular calcium ion levels and protein kinase C theta phosphorylation in human mast cells. British journal of pharmacology. 145, 934-944 (2005).

7 S. M. Thornhill, A. M. Kelly, Natural treatment of perennial allergic rhinitis. Alternative Medicine Review. 5, 448-454 (2000). 8 W. Blok, J. P. Deslypere, P.N. M. Demacker, J. Van Der Ven-Jongekrijg, M. P. C. Hectors, et al, Pro- and anti-inflammatory cytokines

in healthy volunteers fed various doses of fish oil for 1 year. European Journal of Clinical Investigation. 27, 1003–1008 (1997). 9 H. Basciano, L. Federico, K. Adeli, Fructose, insulin resistance, and metabolic dyslipidemia. Nutrition & Metabolism. 2, 5 (2005).10 L. Chatzi, G. Apostolaki, I. Bibakis, I. Skypala, V. Bibaki-Liakou, N. Tzanakis, et al., Protective effect of fruits, vegetables and the

Mediterranean diet on asthma and allergies among children in Crete. Thorax 62(8), 677-683 (2007).11 B. De, J. Garcia-Aymerich, A. Barraza-Villarreal, J. Ant, I. Romieu, Mediterranean diet is associated with reduced asthma and

rhinitis in Mexican children. Allergy, 63(10), 1310–1316 (2008). 12 L. Garcia-Marcos, I. M. Canflanca, J. B. Garrido, A. L. Varela, G. Garcia-Hernandez, F. G., et al, Relationship of asthma and

rhinoconjunctivitis with obesity, exercise and Mediterranean diet in Spanish schoolchildren. Thorax 62(6), 503-508 (2007). 13 Hollman, P. C. H., van Trijp, J. M. P., & Buysman, M. N. C. P. (1997). Relative bioavailability of the antioxidant flavonoid quercetin

from various foods in man. FEBS letters, 418(1-2), 152-156. 14 A. Linneberg, T. J∅rgensen, N. H. Nielsen, F. Madsen, L. Fr∅lund, et al, The prevalence of skin-test-positive allergic rhinitis in

Danish adults: two cross-sectional surveys 8 years apart, The Copenhagen Allergy Study. Allergy. 55, 767-772 (2000).

less damage and irritation of the host tissue, mainly in the late phase reaction described above. While established treatments are still being used, some natural substances are beginning to be recognized for their effects on alleviating allergy symptoms. Quercetin is a bioflavonoid found in many fruits and vegetables. Multiple studies have shown that it stabilizes mast cells, preventing the release of their pro-inflammatory contents, which in turn prevents the immediate and late-phase reactions.6 A clinical study has shown that quercetin can be used as a primary therapy or along with conventional therapies for allergy symptoms.7 Quercetin has no contraindications with allergy medications because it affects the source of histamine rather than the receptors.6

One natural substance that has garnered more press than quercetin is fish oil. Fish oil also blocks some of the pro-inflammatory cytokines in the late-phase reaction and contains the anti-inflammatory fatty acids eicosapentanoic acid (EPA) and docosahecaenoic acid (DHA), commonly called the omega 3 fatty acids.8 These fatty acids have been shown to counter the effects of the pro-inflammatory arachidonic acid, which is made as a result of the lipid mediators in the late-phase reaction. Although these compounds can greatly alleviate allergy symptoms, they are scarcely incorporated in the modern diet. Due to convenience, high fructose corn syrup and refined vegetable oils have often taken the place of fruits and natural fats. There is evidence that the presence of these compounds, along with the scarcity of fruits and vegetables, facilitate the

The Impact of Non-Enzymatic Glucose SensorsBY SOHAIB HASHMI

Accurate determination of glucose concentrations has been of significant scientific interest, primarily because of its applications in treating patients with diabetes mellitus. The incidence of diabetes in the United States is 25.8 million people (8.3% of the population), with seven million undiagnosed cases (28% of all cases).1 Current research is focused on the development of new techniques and technologies to increase the sensitivity, reliability and speed of response and to reduce the cost of sensors used for glucose determination, thereby improving the diagnosis of diabetes. The technique reviewed here specifically involves the use of transition metal nano-particles held in a carbon nanotube framework that can serve as non-enzymatic catalysts in glucose sensors. Traditionally, the most commonly used devices have been based on enzymatic glucose detection, but many other approaches are being considered, including optical techniques like infrared spectroscopy and photo acoustic spectroscopy, the electrochemical approach and colorimetry.2 Although such techniques are non-invasive and have the advantage of serving as continuous glucose-monitoring devices, the electrochemical approach appears to be the most promising because of its simplicity, high reliability, sensitivity and selectivity. Additional benefits include low cost, compatibility for miniaturization and better ease of use.3

Amperometric glucose sensors use the oxidation of glucose to establish a potential across two electrodes, which in turn generates a current. They can be classified into two major types: enzymatic and non-enzymatic. Groundbreaking research into enzyme electrodes and biosensors during the 1960s led to the employment of enzymes in glucose sensors. This subsequently paved the way for over four decades of rapid development in the field.4,5 Electrochemical detection of glucose makes use of the enzymes glucose dehydrogenase (GDH) or glucose oxidase (GOx).6-12

There are several major shortcomings associated with enzyme-based sensors. They lack stability and reproducibility, which is a consequence of the intrinsic nature of enzymes. Further, enzyme activity is easily influenced

increase of pro-inflammatory cytokines associated with allergy symptoms as well as chronic inflammation.8,9 Three studies done in Mexico, Spain and Greece showed that children fed the Mediterranean diet (high in fruits, vegetables, fish, and olive oil), suffered significantly less from allergy symptoms than children who did not.10,11,12

Undoubtedly, there are many pos-sible alternatives for alleviating allergy symptoms. Billions of dollars have been spent on developing effective drugs that can allay and possibly eliminate symp-toms with few side effects. However, there are also dietary changes that could make one more resistant to the effects of pol-len and dander. Increasing one’s intake of fruits and vegetables (notably apples, onions, and capers) can stabilize mast cells and prevent the pro-inflammatory response. Also, increasing one’s consump-tion of fatty fish can mollify the symp-toms of allergies once the pro-inflamma-tory response has begun.13

The increasing prevalence of allergies can be attributed to the lack of certain compounds in the modern diet.14 Today, the proportion of pro-inflammatory foods that contain high fructose corn syrup and hydrogenated oils has risen in the modern diet when compared to anti-inflammatory foods like fish, fruits, and vegetables. Although natural compounds take longer to relieve symptoms, the benefits can be extensive. Fish oil has been attributed to decreased incidences of stroke and heart attack, a better mood, and a healthier muscle to fat ratio.Therefore, choosing more natural foods for one’s diet can lead to long-term allergy relief as well as many other health benefits.


by temperature, pH, salt and humidity, as well as toxic chemicals and secondary metabolites. Even though GOx is relatively stable compared to other enzymes, these sensors are still vulnerable to damage by thermal and chemical agents.3 The enzymes are also expensive, and their sensitivity to external variables such as temperature adds to the expense of GOx- and GDH-based glucose sensors. Due to the inherent problems associated with enzyme-based biosensors, researchers are attempting to determine glucose concentration by other electrochemical methods.3,12

One non-enzymatic approach employs a direct amperometric sensor, which produces a reading based on the current response of glucose oxidation at the electrode surface.3,8 Nanostructured materials such as carbon nanotubes (CNTs) have useful and distinct characteristics, including extraordinary optical, mechanical and electrical properties. Therefore, CNT-transition metal nanocomposites are being investigated as non-enzymatic electrocatalysts for developing glucose sensors.

PROPERTIES OF CARBON NANOTUBE/TRANSITION METAL COMPOSITES THAT AID CATALYSISCNTs are becoming increasingly popular as electrode materials. They have a large surface area, high electrical conductivity, outstandingly strong mechanical properties and very high stability. Discovered by Sumio Iijima in 1991, CNTs emerged as excellent candidates with numerous nanotechnological applications, including acting as fillers in polymer matrices, molecular tanks and biosensors. Catalytic activity is known to rise with increasing surface area. Recent research has shown that properties

of catalysts can be altered by changing the properties of the material being used. This includes grain size, texture and surface profile. As a result, engineering catalysts based on nano-sized particles that maximize surface area would improve the catalyst’s effectiveness to a much greater extent than non-enzymatic biosensors. Based on such research, many catalytic metal and alloy nanoparticles have been embedded into CNTs in order to produce even more sensitive and selective non-enzymatic glucose sensors.3,5,10,13-17

Before metal nanoparticles are embedded into CNTs, it is necessary to add chemical groups to the tube surfaces. This process, known as functionalization, is essential for the embedding of the metal nanoparticles into the CNTs. The number of oxygen-bearing groups on the CNTs can be increased, allowing the properties of the metal catalysts loaded on the CNTs to be modified via oxidative treatment.7 The CNT surfaces may be treated with reagents to introduce functional groups, which facilitate the attachment of metal nanoparticles to the CNT (Figures 1 and 2).11,17-19

ELECTROCATALYSIS OF GLUCOSEIt is imperative that the efficiency of CNT-metal nanoparticle composites be assessed. Two factors can be used to explain the electrocatalytic properties of CNT-metal nanoparticle catalysts. The first is the catalytic activity of the metal nanostructures, and the second is the electrical network resulting from the direct binding of the nanoparticles with the CNT walls.3 The catalytic properties of transition metals are aided by their nanostructure state and the strong electrocatalytic activity of the composites. The CNTs allow the metal nanoparticles to be well distributed, increasing the effective surface area of the catalyst and facilitating the

Images of Single-Walled Nanotube structure (A), Palladium/Single-Walled Nanotube composite (B), and Palladium Nanoparticles (C).

Non-enzymatic glucose sensors are involved in glucose oxidation, and have important implications for accurately determining glucose concentrations in patients with diabetes mellitus. It has been demonstrated that single walled carbon nano-tubes (CNTs) are capable of higher rates of glucose electrocatalysis when combined with nanoparticles (B) such as palladium (C), compared to CNTs lacking nanoparticles (A) .

Carbon Nanotubes and Palladium Nanoparticles


References

1 Association, A. D. (2011). 2011 National Diabetes Fact Sheet. American Diabetes Association.

2 Morikawa, M., Kimizuka, N., Yoshihara, M., Endo, T. (2002). New Colorimetric Detection of Glucose by Means of Electron-Accepting Indicators: Ligand Substitution of [Fe(acac)3−n(phen)n]n+ Complexes Triggered by Electron Transfer from Glucose Oxidase. Chem. Eur. J., 8, 5580-5584.

3 Meng, L., Jin, J., Yang, G., Lu, T., Zhang, H., & Cai, C. (2009). Nonenzymatic electrochemical detection of glucose based on palladium-single-walled carbon nanotube hybrid nanostructures. Anal Chem, 81(17), 7271-7280.

4 Clark, L. C., Jr., & Lyons, C. (1962). Electrode systems for continuous monitoring in cardiovascular surgery. Ann N Y Acad Sci, 102, 29-45.

5 Updike, S. J., Hicks, G.P. (1967). Enzyme electrode. Nature, 214, 986-988.6 Du, P., Zhou, B., Cai, C. (2008). Development of an amperometric biosensor for

glucose based on electrocatalytic reduction of hydrogen peroxide at the single-walled carbon nanotube/nile blue A nanocomposite modified electrode. J Electroanal Chem, 614, 149-156.

7 Jia, W. Z., Hu, Y. L, Song, Y. Y, Wang, K, Xia, X. H. (2008). Highly selective amperometric glucose microdevice derived from diffusion layer gap electrode. Biosens Bioelectron, 23(6), 892-898.

8 Li, X., Zhu, Q., Tong, S., Wang, W., Song, W. (2009). Self-assembled microstructure of carbon nanotubes for enzymeless glucose sensor. Sensors and Actuators B: Chemical, 136, 444-450.

9 Shan, C., Yang, H, Song, J, Han, D, Ivaska, A, Niu, L. (2009). Direct electrochemistry of glucose oxidase and biosensing for glucose based on graphene. Anal Chem, 81(6), 2378-2382.

10 Wang, Z., Liu, S., Wu, P., Cai, C. X. (2009). Detection of glucose based on direct electron transfer reaction of glucose oxidase immobilized on highly ordered polyaniline nanotubes. Anal. Chem., 81, 1638-1645.

11 Wu, L., Zhang, X., Ju, H. . (2007). Amperometric glucose sensor based on catalytic reduction of dissolved oxygen at soluble carbon nanofiber. Biosens. Bioelectron., 23(4), 479-484.

12 Zhao.M, W. X., Cai.CX. (2009). Polyaniline Nanofibers: Synthesis, Characterization, and Application to Direct Electron Transfer of Glucose Oxidase. J. Phys.Chem.C, 113, 4987-4996.

13 Liao-Chuan Jiang, W.-D. Z. (2010). A highly sensitive nonenzymatic glucose sensor based on CuO a. nanoparticles-modified carbon nanotube electrode. Biosensors and Bioelectronics, 25, 1402-1407.

14 Male, K. B., Hrapovic, S., Liu, Y.L., Wang, D.S., Luong, J.H.T (2004). Electrochemical detection of carbohydrates using copper nanoparticles and carbon nanotubes. Anal. Chim. Acta 516, 35-41.

15 Xiao, F., Zhao, F., Mei, D., Mo, Z., & Zeng, B. (2009). Nonenzymatic glucose sensor based on ultrasonic-electrodeposition of bimetallic PtM (M=Ru, Pd and Au) nanoparticles on carbon nanotubes-ionic liquid composite film. Biosens Bioelectron, 24(12), 3481-3486.

16 Xiao, F., Zhao, F., Zhang, Y., Guo, G., Zeng, B. (2009). Ultrasonic Electrodeposition of Gold−Platinum Alloy Nanoparticles on Ionic Liquid−Chitosan Composite Film and Their Application in Fabricating Nonenzyme Hydrogen Peroxide Sensors. J. Phys. Chem. C, 113, 849-855.

17 Zhu, H., Lu, X., Li, M., Shao, Y., & Zhu, Z. (2009). Nonenzymatic glucose voltammetric sensor based on gold nanoparticles/carbon nanotubes/ionic liquid nanocomposite. Talanta, 79(5), 1446-1453.

18 Wang, S., Jiang, S.P., Wang, X. . (2008). Polyelectrolyte functionalized carbon nanotubes as a support for noble metal electrocatalysts and their activity for methanol oxidation. Nanotechnology, 19, 265601.

19 Wu, H. X. C., W.M.; Li Y.; Liu, G.; Wen, Y.; Yang, H.F.; Yang, S.P. (2010). In situ growth of copper nanoparticles on multiwalled carbon nanotubes and their application as non-enzymatic glucose sensor materials. Electrochimica Acta, 55, 3734-3740.

interaction of nanoparticles and substrate molecules. In one study, the absence of CNTs with a single layer of carbon atoms resulted in poor dispersal and clumping of palladium nanoparticles, reducing their efficiency as catalysts (Figure 2).3

Furthermore, one study demonstrated the importance of nanoparticles in enhancing the electrocatalytic activity of non-enzymatic glucose sensors. It was shown that the addition of copper nanoparticles to multi-layered CNTs increased the rate of glucose catalysis compared to multi-layered CNTs lacking the nanoparticles (Figure 1). In addition, it was demonstrated that without the presence of a polyethylenimine functional group on the multi-layered CNT, the electrode was shown to produce an unstable and irreproducible response.19 This illustrates the importance of introducing a functional compound in the engineering of a CNT-based non-enzymatic glucose sensor. Finally, a final study was able to confirm that the combination of a CNT with a functional group and metal nanoparticle composites were most effective in electrocatalysis of glucose.3

REPRODUCIBILITY, STABILITY, AND ANTI-INTERFERENCE PROPERTIESLong-term reproducibility is an important factor in engineering a marketable non-enzymatic glucose sensor. Multi-layered CNTs that are combined with functional groups and nanoparticles showed no noticeable decrease in their activity towards glucose when stored at 40oC for a period exceeding a month.19 Another study was also able to prove that the current response of an electrode modified with copper oxide nanoparticles after 30 days was 90% of the current response at the original electrode. The sensors were also unaffected by the numerous oxidative species such as carbohydrate compounds and acids, as well as the high concentration of chloride ions present in blood.13 These studies provide evidence supporting the high degree of reproducibility and stability of non-enzymatic glucose sensors.

CONCLUSIONCNT-metal nanoparticle composites have displayed great potential as non-enzymatic glucose sensors.

High magnification image of copper/carbon nanotube composite structures

The electrochemical approach, which has the advantage of being a non-invasive, continuous glucose-monitoring technique, appears to be the most promising non-enzymatic option for glucose detection.

The catalysts in the studies discussed here showed outstanding sensitivity, high selectivity, good stability, reproducibility and excellent resistance to the presence of interfering agents. They overcome some of the problems with enzymatic sensors, such as those of pH sensitivity, temperature sensitivity and stability. With work still in the experimental stages, the cost effectiveness of such sensors has not yet been conclusively studied. Before such sensors can be considered as replacements for more conventional methods, the costs of using nanomaterials must be assessed. Nevertheless, the results of the trials using such composites are very promising.


Consider the case of two British families affected by the rare genetic disorder called harlequin ichthyosis. Lucy and Hannah Betts, and Dana and Lara Bowen, are two pairs of sisters who all suffer from a rare skin disorder that makes their epidermis replicate at ten times the normal rate.6 DNA testing has shown that both sets of sisters are likely distantly related, sharing a common ancestor who was the first carrier of the mutation. This devastating disorder usually causes fatal infections during the first week of a newborn’s life; however, the girls survived due to medical advances in dermatology. Professor John Harper of Great Ormond Street Hospital, London, stated that children affected by this condition are “just not compatible with living.”6 However, exceptionally potent moisturizers have been developed that greatly increase the expected life span of individuals afflicted by this disease. The longest living survivor in the UK is Nelly Shaheen, age 26.7 Assuming that the Betts and Bowen sisters maintain their disease management habits, they are expected to have a similarly extended lifespan. As with CF, the longevity afforded to these individuals with otherwise lethal diseases also creates additional risks. If these individuals choose to have children, they could pass their deleterious genes onto their offspring. However, many prenatal diagnostic tests are available to help prepare parents for an ill child or even prevent undesired genes from ending up in their offspring’s genome. The primary test available to pregnant women is maternal blood screening, commonly known as the “triple screen” test. This procedure measures the concentrations of three substances in the mother’s body:8 alpha-fetoprotein, associated with neural tube defects;9 unconjugated estriol, a Down syndrome indicator;10 and human chorionic gonadotropin, which may auger an abnormal pregnancy.11

Another common prenatal test is ultrasound sonography, a procedure in which high frequency sound waves are directed at the developing baby. The reciprocating echo produces a representation of the fetus’s anatomy.12 It is frequently performed regardless of the results of the triple screen test, and can identify a baby’s gender. However, this

Scientists have the ability to select embryos that have not inherited the

genetic abnomalities suffered by the parents

The Expanding World of Prenatal Testing

BY EGOR BUHARIN

Between 1820 and 2006, medical and nutritional advances have been credited with nearly doubling the average human life span from 42 to 77 years.1 Breakthroughs have allowed millions of individuals suffering from genetic abnormalities to enjoy an improved quality of life. At the same time, individuals who, in another time or place, would have succumbed to their illnesses, are passing on their genes to future generations. In so doing, they spawn generations who may in the long run prove more compromised genetically than their parents. Through the influence of modern medicine on the expansion of genetic selection, a new scientific field has emerged, which gives parents a glimpse of their potential offspring before birth and can provide the potential for deciding which genes are carried forward to the next generation. The ability of modern scientists to manipulate genetic selection is evident from recent advances in the treatment of cystic fibrosis (CF). CF is an autosomal recessive genetic disorder characterized by abnormal secretions of the respiratory, digestive, and reproductive tracts.2 This debilitating disease often kills its victims at relatively young ages; however, increasing numbers of individuals are now living to reproductive ages and having children.3,4 Increased longevity is largely due to improvements in the deployment of antibiotics and in pulmonary

and chest physical therapies.2 In addition, researchers have worked to address the issue of masculine infertility in CF sufferers. While more than 95% of CF males lack both vasa deferentia and are ordinarily infertile, in vitro reproductive techniques offer a viable option for bypassing this obstruction and making fatherhood a very real possibility

for these individuals.5 Such medical interventions unfortunately come at great risk to the offspring—at best, the child is destined to be a carrier of the mutated CF channel gene.

New technology could be a major step towards putting evolution into the hands of mankind

THE DIFFERENCE BETWEEN:

CYSTIC FIBROSIS• Geneticdisorder

(autosomal recessive)• Causesthetheproduction

of mucus which blocks passages throughout the body

• Mayresultinearlydeath

HARLEQUIN ICHTHYOSIS• Geneticdisorder

(autosomal recessive)• Causeshard,thickskinthat

limits movement of body parts like arms, legs, and chest

• Mayleadtobreathingdifficulties and respiratory failure

Source: Genetics Home Reference (http://ghr.nlm.nih.gov)


References

1 Cutler, D. (n.d.). The determinants of mortality. The National Bureau of Economic Research. Retrieved March 4, 2011, from http://www.nber.org/papers/w11963

2 McCance, K. L., Huether, S. E., & Parkinson, C. F. (2006). Pathophysiology: the biologic basis for disease in adults & children : study guide and workbook (5th ed.). St. Louis, Missouri : Mosby.

3 Dodge, J., Lewis, P., Stanton, M., & Wilsher, J. (2006, December 20). Cystic fibrosis mortality and survival in the UK: 1947â€“2003 . European Respiratory Journal. Retrieved March 4, 2011, from http://erj.ersjournals.com/content/29/3/522.full

4 Boyd, J. (2004, June 15). Fertility and pregnancy outcomes in men and women with cystic fibrosis in the United Kingdom . Oxford Journals | Medicine | Human Reproduction. Retrieved March 4, 2011, from http://humrep.oxfordjournals.org/content/19/10/2238.abstract

5 Popli, K., & Stewart, J. (n.d.). Informa Healthcare - Human Fertility - 10(4):217 - Summary . An Error Occurred Setting Your User Cookie. Retrieved March 4, 2011, from http://informahealthcare.com/doi/abs/10.1080/14647270701510033?2

6 The girls with too much skin | Etraordinary People | TV Highlights | Throng. (2008, March 12). Throng | UK’s TV watching community. Retrieved March 4, 2011, from http://www.tvthrong.co.uk/extraordinary-people/the-girls-with-too-much-skin

7 More than skin deep for Nelly Shaheen - Post Features - Life & Leisure - Birmingham Post. (2010, December 17). Birmingham Post - local news, Birmingham business, guide, politics & more. Retrieved March 4, 2011, from http://www.birminghampost.net/life-leisure-birmingham-guide/postfeatures/2010/12/17/more-than-skin-deep-for-nelly-shaheen-65233-27824132/

8 Gazis-Sax, L. (2010, October 21). 1. What are the screens?. Welcome to stason.org. Retrieved March 4, 2011, from http://stason.org/TULARC/child-parent/pregnancy-screening/1-What-are-the-screens.html

9 Patrakka, J., Martin, P., Salonen, R., Kestila, M., Ruotalainen, V., & Mannikko, M. (2002, May 4). ScienceDirect - The Lancet : Proteinuria and prenatal diagnosis of congenital nephrosis in fetal carriers of nephrin gene mutations. ScienceDirect - Home . Retrieved March 4, 2011, from http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1B-45XXHHB-F&_user=489256&_coverDate=05/04/2002&_rdoc=1&_fmt=high&_orig=gateway&_origin=gateway&_sort=d&_docanchor=&view=c&_searchStrId=1664723077&_rerunOrigin=google&_acct=C000022721&_version=1&

10 Cuckle, H. (n.d.). Measuring unconjugated estriol in maternal serum to screen for Down Syndrome. Clin Chem. Retrieved March 4, 2011, from www.clinchem.org/cgi/reprint/38/9/1687.pdf

11 Vorvick, L. (2008, October 28). HCG blood test - quantitative: MedlinePlus Medical Encyclopedia. National Library of Medicine - National Institutes of Health. Retrieved March 4, 2011, from http://www.nlm.nih.gov/medlineplus/ency/article/003510.htm

12 Gerards, F., Twisk, J., Fetter, W., Wijnaendts, L., & Vugt, J. V. (n.d.). Predicting pulmonary hypoplasia with 2- or 3-dimen... [Am J Obstet Gynecol. 2008] - PubMed result. National Center for Biotechnology Information. Retrieved March 4, 2011, from http://www.ncbi.nlm.nih.gov/pubmed/18166330

13 Santrock, J. W. (2011). Life-span development (13th ed.). New York: McGraw-Hill.14 Gene responsible for severe congenital skin disease, Harlequin Ichthyosis, identified by Queen Mary team. (2005,

March 11). Medical News Today: Health News. Retrieved March 4, 2011, from http://www.medicalnewstoday.com/articles/21075.php

15 IVF worldwide unit directory Preimplantation Genetic Diagnosis (PGD) | Education. (n.d.). IVF worldwide unit directory .. Retrieved March 4, 2011, from http://www.ivf-worldwide.com/Education/preimplantation-genetic-diagnosis-pgd.html

16 Haung, C. C., Lu, R. B., Shi, M., Yen, C., & Haung, S. (n.d.). Wolters Kluwer Health. LWW Journals . Retrieved March 4, 2011, from http://journals.lww.com/jpharmacogenetics/Abstract/2011/02000/Association_study_of_the_dopamine_transporter_gene.5.aspx

17 McEvoy, B. (n.d.). Genetics of human height. [Econ Hum Biol. 2009] - PubMed result. National Center for Biotechnology Information. Retrieved March 4, 2011, from http://www.ncbi.nlm.nih.gov/pubmed/19818695

method may not be ideal for detecting many genetic abnormalities, as the image only provides broad structural information. Upon finding a deformity using ultrasound sonography, physicians would likely follow up by performing a fetal MRI.13 This procedure provides a more detailed image of the fetus, but its uses are limited to finding certain disorders of the central nervous system, thorax, gastroinestinal tract, reproductive system, or placenta.13 Techniques also exist to directly test fetal tissue. In chorionic villi sampling, a small piece of the placenta is excised to provide more information about the fetus, including the presence of chromosomal abnormalities. Unfortunately, this invasive procedure risks damage and limb deformation to the developing baby. Amniocentesis is a similar procedure involving aspiration of a sample of the amniotic fluid, which contains fetal cells that can be tested. This procedure also has its disadvantages, as it increases the chance of miscarriage. Such unfortunate consequences of screening often make parents apprehensive and reluctant. While these tests provide useful information regarding the inheritance of genetic disorders, they are not capable of preventing the defects. However, novel preimplantation genetic diagnosis (PGD) technology makes such genetic selection possible. PGD is the process of identifying genetic disorders in unfertilized and fertilized oocytes, day three cleavage-stage embryos, and early embryonic cell clusters (blastocysts). Often, six blastocysts developed from artificial insemination are tested prior to implanting the embryos into the mother; removal of merely one cell from the blastocyst for testing is entirely harmless to the development of the potential child. The genetic components of the cells are scanned for abnormalities, isolating the most “genetically-superior” blastocysts. Any embryos determined to contain defects may therefore be discarded, without implantation. PGD is most commonly used by couples who are at high risk of conceiving a child with genetic disorders, such as mothers suffering from harlequin ichthyosis. In 2005, a team of researchers at Barts and The London School of Medicine and Dentistry, London, located the single gene responsible for this devastating skin disorder.14 Now that the mutation has been identified, PGD may help Lucy, Hannah, Dana, and Lara raise healthy children spared of disfigurement and the interminable suffering they would have had to endure. Sometimes seen as the ultimate in preventative care, PGD can save countless people from suffering hereditary disorders. It is already being implemented to prevent the conception of children who would suffer from abnormalities like deafness, CF, muscular dystrophy and Down syndrome.15 Scientists have the ability to select embryos that have not inherited the

genetic abnormalities carried and/or suffered by their parents. This trend has the potential to eventually eradicate many hereditary diseases; with each subsequent generation, the human gene pool would harbor fewer of the genetic abnormalities that cause severe disorders and illnesses. It is important to keep in mind that PGD use is not limited to the eradication of disease. PGD has also been used for choosing a potential child’s eye color and gender. With every passing year, scientists are discovering more about the human genome, including which alleles characterize our personalities and physical appearance.16,17 Such deciphering of the human genetic make-up is likely to permit the customization of children by future parents. It is conceivable that enhanced understanding of the human genome may allow scientists to locate the genes for muscle development and even intellect; traits that parents may want their children to inherit. This recent and exciting field of medicine has dramatically propelled studies of genomics and bioethics. PGD has tremendous potential to impact the world; it is a versatile procedure capable of detecting myriad of genetic diseases. In essence, this new technology could be a major step towards putting evolution into the hands of mankind.

PRENATAL DIAGNOSTIC TESTS

“TRIPLE SCREEN” TESTmaternal blood screening test to measure concentrations of different substances in mother’s body

ULTRASOUND SONOGRAPHYhigh frequency sound waves directed at the fetus for representation of fetus’s anatomy

CHORIONIC VILLI SAMPLINGextracted placenta is examined for more information of the fetus

PRE IMPLANTATION GENETIC DIAGNOSIScells from blastocyst are used for testing of abnormalities and defective embryos can be discarded without implantation

New technology could be a major step towards putting evolution into the hands of mankind


A CALL TO ACTION ARISING FROM INDUSTRY CHALLENGESThe demand for pharmaceutical products around the world has increased dramatically in recent years. By 2020, 9.4% of the world’s 7.6 billion people will be 65 or older, and four out of five will take at least one prescription medication. Further inflating the demand for pharmaceutical products are the surging demands from emerging markets, such as India and China.1 Meeting this demand and penetrating these new markets, however, has not been easy for many companies. Exacerbated by home-market challenges such as healthcare policy reform and stricter regulatory agencies, the problems facing the pharmaceutical industry have long been in the making.2 A perfect storm of imminent patent expirations, sharp volume increases in sales of generic medicines and growing regulatory costs is expected to significantly impact the profitability of many major pharmaceutical companies. The eight leading firms (by sales) project a 14% to 41% decrease in revenue due in large part to a patent cliff between now and 2012.1

The healthcare industry is one of the most innovation-centric, spending over $1.12 billion in corporate R&D in 2009, a figure that is second only to the computing and electronics industry.3 The cost to fully develop a drug, however, is estimated to be approximately $1 billion, and the time horizon approximately 10 to 15 years. The underlying firm-level issue in pharma today is the decline in innovation productivity; more simply, fewer new drugs are green-lit for commercialization. Total R&D expenditure has soared in the last two decades, while regulatory approval of new molecular entities and biologics (hereafter referred to collectively as NMEs) has decreased nearly 50% since the mid-1990s peak.1 However, in light of today’s medical and technological breakthroughs, such as the human genome project and computer modeling of compounds, the pipeline’s input-output misalignment seems intuitively illogical. The problem facing the industry is therefore as such: How does a pharmaceutical company rejuvenate its ailing pipeline? Pharmaceutical giants are exploring many options to combat this problem. Three firms in particular—Eli Lilly, GlaxoSmithKline (GSK), and Pfizer—have developed skunkworks units within their main labs. A skunkworks is traditionally a small R&D group that operates mostly separately from the day-to-day directives of corporate management. They typically have a singular focus, but they are otherwise free to determine how to reach the end goal. From a pharmaceutical lens, that singular focus is on driving proof-of-concept (PoC) early and cheaply without the constraints of firm-wide research methodologies. Achieving PoC is linked with increasing the probability of technical success, or the chances of a drug making it to market. It is because of this increased likelihood that the focus of pharma skunkworks should be to achieve PoC

in order to maximize innovation productivity. This strategy may help the pharmaceutical industry refocus R&D activities on the pursuit of innovation without being distracted by external market and profitability factors.

A SKUNKWORKS FOR PHARMA: FOCUSING ON PROOF-OF-CONCEPTThe term “skunkworks” originated as a nickname for Lockheed Martin’s Advanced Development Programs, whose first project was developing a fighter jet for the U.S. government during World War II. Its mantra is “quick, quiet and quality”. The skunkworks strategy has since spilled over into other manufacturing and engineering industries as a method of innovation management. It is characterized by a small research team separated from the ongoing part of the business for most of its activities. The team typically has complete autonomy to work on its product or process, free from corporate control over procedures, milestones and budgeting.4 Anecdotal evidence has shown that it can still be effective today. The comparable goal of pharmaceutical skunkworks is to establish PoC quickly and efficiently. PoC is a decision milestone within the development process that establishes whether the proposed chemical mechanism has the desired effect in humans. There are two primary benefits to establishing PoC early on. First, PoC encourages efficiency by helping to confirm or reject the proposed molecule’s validity early on, thereby eliminating the potential for wasteful investment. Secondly, it helps to increase the probability of achieving success. As a successful indicator of established effectiveness in humans, a PoC approved molecule will have an enhanced probability of gaining NME approval.5-6

Because PoC can be so valuable for firms in evaluating their pipelines, it is ideal to reach this milestone as early as possible. Pharmaceutical skunkworks lend themselves to this goal of speed and efficiency. These smaller groups of scientists are given the goal of proving or disproving PoC (Bonabeau et al., 2008). The flat and small structure of a skunkworks results in lower operating costs and constrains the number of researchers in a group. It also confers the unit greater freedom to determine its own course of action, developing an “act like an owner” culture.7 The three qualities of small, autonomous and entrepreneurial contribute to a fast-paced, empowered environment that vets PoC quickly and efficiently. Cartwright et al. point out two underlying concepts of the PoC definition: First, PoC determines whether research on the molecule should continue; secondly, PoC can appear at any stage in the development process, depending on the company’s R&D strategy.8 A two-step process is used to achieve PoC. The first step is to define the intended effect of this drug on the human body, while the second is to individually evaluate the contribution of each chemical element in the proposed molecule toward the previously-established effect. The pharma-adapted skunkworks model has several limitations. The singular focus on PoC could delay a molecule’s

Skunkworks: Stimulating Innovation in the Pharmaceutical Industry

BY JACLYN CHEN, HIND HASSAN, TRISH MANTRI, CRISTINA MASSON


Want more Synapse? Visit our website at www.upennsynapse.com.

progression toward other milestones that it inevitability must achieve, thereby limiting how soon a firm can bring a new drug to market.6 Additionally, not all types of molecules are considered suitable for a PoC-centered approach. Molecules without predictive biomarkers often have too many other biomarkers that could mistakenly imply efficacy. Because of this, they often erroneously fail clinical trials, creating a false negative error. Similarly, molecules with well-validated mechanisms elicit high levels of confidence from researchers; spending time on PoC therefore simply elongates the process without adding any value.9 Because this strategy may merely reorganize these decision frames, it begs the question of whether the skunkworks model actually reduces the longevity of the drug development process.9 With these limitations in mind, it is important that pharma companies deploy the skunkworks strategy only when it can add value. The pairing of skunkworks and PoC is a novel approach to structuring pharmaceutical R&D. As evidenced by GSK, Pfizer, and Lilly, there is a trend toward skunkworks in R&D. We next evaluate whether the creation of these PoC-oriented skunkworks teams actually leads to more innovation.

ANECDOTAL EVIDENCE OF SKUNKWORKS IN THE INDUSTRYThis proposed solution to transform the previously bureaucratic R&D departments into smaller, flexible sub-units was the first attempt to stimulate innovation by modeling entrepreneurial companies and capitalizing on the success of Lockheed Martin’s skunkworks. We chose to investigate three companies that were chosen based on 2010 sales revenue and the presence of independent, entrepreneurial, small-scale R&D divisions.10

ELI LILLYPerhaps the most notable pharmaceutical skunkworks is Lilly’s Chorus. A separate entity from Lilly Research Laboratories (LRL), the corporate R&D department, Chorus is unique in its process of filtering molecules to reach clinical trials. The idea is to separate early and late stage drug development, and in doing so, to focus Chorus’ R&D efforts solely on reaching PoC. Lilly has been able to identify viable drugs at twice the speed and at one-third the cost of drugs developed in the corporate R&D labs.6 Chorus advances these “shortcuts” to PoC by outsourcing non-critical steps such as chemical testing and clinical trial execution. The result is faster, cheaper development of drug candidates that have already been proven effective in human trials. Chorus’s flat organizational structure is similar to that of flexible biotech companies and aims to fail molecules early, which, in theory, increases the speed and frequency of “true” innovation. As one of the rare units of Lilly that is not located on the main corporate campus, Chorus manages an independent portfolio of drugs and makes all decisions pertaining to those molecules. The scientists who work at Chorus are carefully selected for their entrepreneurial and outside-the-box thinking, which enables the group to function with fewer employees than in a typical LRL group.

GLAXOSMITHKLINEEight years following the merger between U.K.-based Glaxo Wellcome and SmithKline Beecham, GSK was disappointed with R&D productivity within its Centers of Excellence for

Drug Development (CEDD). The CEDDs were further divided into Discovery Performance Units (DPUs), as management credited the lack of success of the CEDDs to their size. The DPUs were created as smaller, multidisciplinary teams to focus on specific drug pathways or specialized research.11 Whereas Lilly’s Chorus aims to advance all potential molecules to PoC, each DPU focuses on reaching PoC for molecules in a specific therapeutic space. GSK attempts to increase efficiency by having DPUs compete against one another for internal funding, but it grants DPUs budgetary discretion once they receive their funding. Furthermore, most DPUs flaunt their own names, logos and organizational structures as a reminder of their separation from parent-GSK.12 As long as their productivity levels remain high and their spending does not exceed budgeted allotments, DPUs maintain their autonomy from parent-GSK. Whatever the set-up and structure, each DPU is focused on generating tangible results. For example, one DPU aims to deliver one successful PoC molecule per year.13 To this end, GSK has given its DPU experiment a three-year trial period between 2008 and 2011 and will determine whether to continue with the DPU structure.

PFIZERIn October 2007, Pfizer launched its Biotherapeutics and Bioinnovation Center (BBC), an umbrella organization consisting of five small, autonomous research and innovation units. The Centers are based on drug compounds as opposed to GSK’s therapeutic spaces or Lilly’s general PoC-focus. These skunkworks units are strategically stationed in the academic and biotechnology centers of the world and away from Pfizer’s corporate headquarters.14

Pfizer emphasizes autonomy as the key to success for the BBC. The units are granted the luxury of independent decision-making in what compounds to explore and how to undertake the research. Previous biotech presidents and founders are typically chosen to run the centers, so BBC work environments exhibit a strong sense of autonomy and entrepreneurialism even from the top.

MEASURING INNOVATIONWhile skunkworks introduce the best elements of innovative environments into the pharmaceutical industry, it is still important to examine pragmatically whether these new R&D units are effective in improving innovation for these large firms. To do this, we compared the increase in innovation produced by these three pharma companies before and after they introduced skunkworks labs into their R&D structure. However, before analyzing the contributions skunkworks have made to pharma innovation, we first define an accurate metric of innovation. The FDA classifies new drug applications based on their chemical composition as either an NME or a Drug Update. Any newly approved drug is considered an NME, while Drug Updates are considered re-classifications of current technology. Thus, the number of NME drug applications filed with the FDA serves as a tangible metric for innovation. Critics of using NME as a definition for innovation cite that some new applications may offer little therapeutic potential as a drug. However, this is less likely to occur since pharmaceutical companies would


rarely invest the substantial time and money necessary if their research did not lead to valuable or significant conclusions.15 In the pharmaceutical industry, R&D is the birthplace for new profitable ventures for a company—either as an NME or a Drug Update. However, for R&D centers focused on innovation, NMEs become the goal for an end product. The number of NME applications filed with the FDA is the one we will use to gauge the success of a skunkworks strategy.

V. AN EVALUATION OF CURRENT SKUNKWORKS INITIATIVESThe skunkworks concept took off nearly a decade ago, with many companies creating their own versions in line with their existing R&D strategies. However, despite the outward commitments to the skunkworks model, more recent events indicate that these companies may be losing faith in the innovative success of their divisions. On one hand, GSK seems committed to the original structure of its skunkworks DPUs. The original units are in place to conduct research with the ultimate goal of PoC. However, recent developments hint at challenges facing GSK by maintaining DPUs. Since “people who like the really entrepreneurial culture of a biotech go to biotechs,” DPUs suffer a mismatch between employee profiles and the prescribed self-initiated innovation. This prevents GSK from capitalizing on the “act like an owner” intent of skunkworks.7 Additionally, autonomy is being threatened as higher-level management has announced that if DPU scientists do not produce innovations, lay-offs may occur.12 Through this growing pressure to innovate, management’s intensified scrutiny conflicts with the original business model of a skunkworks lab.Like GSK, Pfizer also questions the relevance of its skunkworks division. In the latter half of 2009, Pfizer acquired Wyeth, thereby decreasing its need to invest in the BBC.16 Following the resignation of the creator and former CEO of the BBC, Pfizer also pulled out of a real estate deal in San Francisco that would have provided the BBC its own laboratory.17 Instead, Pfizer enveloped the BBC and Wyeth’s biotech arm within its corporate labs. While current Chief Science Officer David Cox is committed to maintaining the small size and entrepreneurial spirit of the BBC, the recent restructuring has ultimately diluted its autonomy.18 Finally, Lilly also questions the direction of its skunkworks project, Chorus. An interview with Joel C. Scherer, Managing Director and Chief Marketing Officer for Chorus, revealed that Chorus’ “business model has evolved considerably. It’s fair to say Lilly no longer considers Chorus as a skunkworks project”.19 While Lilly still intends to “[capitalize] on the Chorus model as a strategic advantage,” it does not seem to be as effective as was hoped for Lilly to increase overall innovation output. Anecdotally, skunkworks are slightly disappointing when it comes to improving innovation pipelines for large pharma companies. Analytically, comparing NMEs approved before and after the introduction of skunkworks is inconclusive. The following table displays this comparison.

Initially it seems that only GSK’s DPUs were successful in increasing the total number of NMEs approved, while the remaining two worsened the parent company’s pipeline approval rate. Despite this cursory evaluation, the analysis can only be deemed inconclusive for multiple reasons. First, these are early numbers gleaned from current access to public records. Current public numbers do not reveal the actual contributions of each skunkworks lab. Secondly, Pfizer’s BBC and GSK’s DPUs have only been established in the past two years. As it takes approximately 10 to 15 years for a drug to move from initial discovery to PoC to finally NME approval, the innovative outputs of these two skunkworks divisions will not fully materialize until 2018, at the earliest. Finally, as early structural challenges face these fledgling labs, it will take even more time to fully establish a successful method to achieving PoC. David Cox, CSO of BBC, states, “it’s unrealistic to think that we will have the answer [to the success of the BBC] in less than three [years]” (Russell, 2009). While Lilly’s annual report indicated that Chorus did indeed save $100 million in R&D expenditure, the innovative productivity of these skunkworks divisions is still up in the air (Ernst & Young, 2010). More time will provide a better indication of the success of these labs, but this will heavily depend on each of these large pharmaceutical firms staying patiently committed to waiting for their theorized success.

Source: Drugs@FDA, FDA Approved Drug Products Database; http://www.accessdata.fda.gov/scripts/cder/drugsatfda/

Parent Company

Skunkworks Division

Initation Year

Total NME Approvals pre-Skunkworks

% of Total NME Approvals pre-Skunkworks

Total NME Approvals post-Skunkworks

% of Total NME approvals post-Skunkworks

GSK DPUs 2007 77 2.60% 55 9.09%

Pfizer BBC 2008 34 8.82% 39 2.56%

Eli Lilly Chorus 2002 266 11.28% 168 2.98%

References

1. PricewaterhouseCoopers (2010). Pharma 2020: The Vision.2. Pharmaceutical Research and Manufacturers of America (2010). Pharmaceutical Industry Profile.3. Jaruzelski, B., & Dehoff, K. (2010, November 3). The Global Innovation 1000: How the Top Innovators

Keep Winning. Strategy and Business, 61. Retrieved March 27, 2011, from http://www.strategy-business.com/article/10408?gko=08375

4. Rich, B. (1991). The Skunk Works Management Style—It’s No Secret. Product and Process Innovation, 1(2), 28-35.

5. DiMasi, J. (2002). The Value of Improving the Productivity of the Drug Development Process, Faster Times and Better Decisions. Pharmacoeconomics, 20(3), 1-10.

6. Bonabeau, E., Bodick, N., & Armstrong, R. (2008). A More Rational Approach to New-Product Development. Harvard Business Review, 8(3), 96-102.

7. Smith, N., & Roberson, T. (2008). Transforming Drug Development, A fully outsourced model. Pharma Focus Asia, 9, 39-41.

8. Cartwright, M., Cohen, S., Fleishaker, J., Madani, S., McLeod, J., Musser, B., & Williams, S. (2010). Proof of Concept: A PhRMA Position Paper With Recommendations for Best Practice. Clinical Pharmacology & Therapeutics, 87(3), 278-285.

9. Longman, R. (2007). Lilly’s Chorus Experiment. In Vivo, 25(2), 35-39.10. Fortune 500 (2010). Fortune 500 - Industries - Pharmaceuticals. Our annual ranking of America’s

largest corporations. Retrieved March 28, 2011, from http://money.cnn.com/magazines/fortune/fortune500/2010/industries/21/index.html

11. GlaxoSmithKline (2009). GSK is Changing: Annual Report 2009. Retrieved March 28, 2001, from http://www.gsk.com/investors/reps09/GSK-Report-2009-full.pdf

12. Whalen, J. (2010, July 1). Glaxo Tries Biotech Model to Spur Drug Innovations. The Wall Street Journal, 256, A1.

13. Senior, M. (2009, October 15). GSK In Tune with Lilly’s Chorus on Cheap-to-PoC Idea. The In Vivo Blog. Retrieved March 28, 2011, from http://invivoblog.blogspot.com/2009/10/gsk-in-tune-with-lillys-chorus-on-cheap.html

14. R&D Locations. (2010). Pfizer Research & Development. Retrieved March 28, 2011, from www.pfizer.com/research/rd_works/rd_locations.jsp

15. Munos, B. (2009). Lessons from 60 years of pharmaceutical innovation. Nature Reviews: Drug Discovery, 8, 959-968.

16. Edwards, J. (2009, July 7). Pfizer to Close S.F. Biotech Center in Favor of Unit Accused in Patent Suit. BNET - The CBS Interactive Business Network. Retrieved March 28, 2011, from http://www.bnet.com/blog/drug-business/pfizer-to-close-sf-biotech-center-in-favor-of-unit-accused-in-patent-suit/2066

17. Leuty, R. (2009, July 7). Pfizer pfudges S.F. pullout. San Francisco Business Times. Retrieved March 28, 2011, from http://www.bizjournals.com/sanfrancisco/blog/2009/07/pfizer_pfudges_bbc_sf_pullout.html

18. Russell, J. (2009, January 20). Programming at Pfizer’s BBC.Bio-IT World. Retrieved March 28, 2011, from www.bio-itworld.com/issues/2009/jan-feb/target-programming-pfizer-cox.html

19. Scherer, J. (2010, November 18). Interview conducted by Jaclyn Chen.20. Ernst & Young (2010). Beyond Borders: Global biotechnology report 2010. Retrieved March 28, 2011,

from http://www.ey.com/Publication/vwLUAssets/Beyond_borders_2010/$File/Beyond_borders_2010.pdf


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